Investigation of the neural basis of expectation-based analgesia in the human brainstem and spinal cord by means of functional magnetic resonance imaging.

PURPOSE: The expected intensity of pain resulting from a noxious stimulus has been observed to have a strong influence on the pain that is perceived. The neural basis of pain reduction, as a result of expecting lower pain, was investigated using functional magnetic resonance imaging (fMRI) in the brainstem and spinal cord. METHODS: Functional MRI studies were carried out in a region spanning the brainstem and cervical spinal cord in healthy participants. Participants were familiarized with a noxious heat stimulus and study procedures in advance, and were informed during each trial that either a heat calibrated to produce moderate pain (Base state), or a temperature 1 °C lower (Low state), would be applied to their hand. However, the Base temperature was applied in every trial. RESULTS: Pain ratings were significantly reduced as a result of expecting lower temperatures. FMRI results demonstrate blood oxygenation-level dependent (BOLD) signal variations in response to participants being informed of the stimulus to expect, in advance of stimulation, and in response to stimulation. Significant coordination of BOLD signals was also detected across specific brainstem and spinal cord regions, with connectivity strengths that varied significantly with the study condition, and with individual pain ratings. The results identify regions that are known to be involved with arousal and autonomic regulation. CONCLUSIONS: Expectation-based analgesia is mediated by descending regulation of spinal cord nociceptive responses. This regulation appears to be related to arousal and autonomic regulation, consistent with the cognitive/affective dimension of pain.

Color adjustment potential of resin composites.

The study objective was to explore a new method for quantifying the color adjustment potential originating from physical translucency on a set of 7 resin composites, and then for testing the hypothesis that color adjustment potential is dependent on the composites and shades studied. Two-composite specimens (an outer base shade with an inner hole filled with inner test shades) and single-composite specimens of all shades were made. A 1-mm circular area, with its center in the middle of the specimen (P0mm), was measured by means of spectroradiometry. A newly developed equation for quantification of the color adjustment potential was tested. Color adjustment potential at P0mm ranged from -0.19 (negative color adjustment/contrast) to 0.61. Within the limitations of this study, a newly developed concept and equation have proved the existence of the physical component of color adjustment of translucent dental materials. Color adjustment potential was dependent on composite and shade.

The pathology of peroxisomal disorders with pathogenetic considerations.

Peroxisomal disorders are rare systemic maladies in which specific major organ systems are typically involved: most importantly the central nervous system (CNS), but also the peripheral nervous system, eyes, liver, adrenal, kidney and skeleton. Zellweger syndrome (ZS) is the most severe of the generalized types and exhibits major neocortical migration defects, less severe and non-inflammatory white matter lesions, and dysmorphic features. In adrenoleukodystrophy (ALD) the major lesion again is in the CNS, but consists of extensive dysmyelination/inflammatory demyelination without neuronal migration defects or dysmorphism. In adrenomyeloneuropathy long tract degeneration of spinal cord, peripheral neuropathy, and variable CNS dysmyelinative to inflammatory demyelinative lesions are the dominant nervous system lesions. Saturated very long chain fatty acids, either free in the cytoplasm of affected endocrine cells or as components of membrane lipids (e.g. gangliosides, glycerophospholipids, and proteolipid protein) in axons or myelin, may be central to the pathogenesis of these neuronal migration defects, dysmyelination/inflammatory demyelination and spinal tract degeneration. Cytokines, particularly tumor necrosis factor-alpha, and delayed cellular hypersensitivity appear to be major secondary pathogenic factors in ALD.

An immunologic assessment of brain-associated IgG in senile cerebral amyloidosis.

Frontal and occipital lobes were taken within four hours of death from four senile patients (77-94 years) and frozen at -70 degrees C. After thawing at room temperature, gray and white matter were separated and subjected to sequential elution at pH 7.4 and pH 2.5. The eluates were processed for isoelectric focusing on 2.5% polyacrylamide gels and stained with silver nitrate; immunoblotting was done on agarose gels and stained by immunoperoxidase for IgG and light chains. Quantitation of the amount of IgG present in neutral and acidic eluates was performed by immunonephelometry and ELISA. Only the neutral eluates contained significant amounts of IgG, which were usually polyclonal. These data indicate that IgG associated with senile cerebral amyloid are not bound to any brain or vascular component and the data do not support the occurrence of an intraparenchymal immune response.

The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications.

Prominent inflammation in the demyelinative lesion of adreno-leukodystrophy (ALD) has suggested an immune-mediated pathogenetic component. Commercially available antibodies to T cells, B cells, macrophages, class I and II molecules, complement, IgG, IgM, IgA, interleukin-1 (IL-1), intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-alpha (TNF) were applied to paraffin sections of formaldehyde-fixed postmortem samples. Twenty-five primary demyelinative lesions from five juvenile ALD, three adult ALD, and three adrenomyeloneuropathic patients were evaluated with appropriate positive and negative controls. Macrophages and astrocytes were the predominant cells detected at the active edge; T lymphocytes, including T4 and CD45R subsets, were nearly as numerous but usually located around vessels within the lesion. B cells and plasma cells, usually containing IgG, were uncommon. The expression of class II molecules, restricted to one adult, was problematic; class I expression was increased in microvascular and other cells. Degraded myelin was labeled with antibodies to C3d and IL-1; IL-1 and ICAM-1 immunoreactivity was seen on microvessels and astrocytes. Tumor necrosis factor-alpha immunoreactivity was detected in macrophages, but more prominently in astrocytes. These data support a natural immune response in the demyelinative lesion of ALD, consisting predominantly of reactive astrocytes, macrophages, T cells and cytokines. A two-stage pathogenetic theory is discussed. The postulated roles of TNF and reactive astrocytes, in concert with a fundamental myelinolytic biochemical defect, suggest a different pathogenetic mechanism and raise novel therapeutic possibilities.

The effects of spinal cord trauma on myelin.

Experimental spinal cord trauma was produced in rats by dropping a 10-g weight from a height of 30 cm upon exposed spinal cord. The histological lesion consisted of edema, necrosis, and hemorrhage. The fine structure of the early traumatic lesion (4 to 12 hours) included granular dissolution of axons and a characteristic vesiculation of myelin. The predominant ultrastructural features of older lesions (12 to 72 hours) were intra-axonal calcification and lipid-laden macrophages. The yield of myelin and the activity of adenosine 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) were reduced by approximately 15% at 4 hours and by 60% at 72 hours. Losses in all myelin proteins were observed, but were most severe and occurred earliest in the basic proteins. The ultrastructural and biochemical alterations observed in this study indicate that proteinase activity is increased and may be partially responsible for the traumatic myelinolysis in experimental spinal cord trauma.

Structural and chemical alterations in the cerebral maldevelopment of fetal cerebro-hepato-renal (Zellweger) syndrome.

The cerebra of four abortuses (estimated gestational age 14-22 weeks), diagnosed as cerebro-hepato-renal (Zellweger) syndrome in utero, were examined morphologically with light microscopic, immunocytochemical and ultrastructural techniques and biochemically with gas liquid chromatographic assays for cholesterol ester fatty acids and plasmalogens. Centrosylvian architectonic abnormalities consisting, in part, of thin cortical plates and broad subcortical heterotopic zones were found in all abortuses. Astrocytes, neuroblasts, immature neurons and radial glia contained abnormal pleomorphic cytosomes, presumably of variable lipid composition. The same areas exhibited increases in cholesterol ester very long chain fatty acids and decreased plasmalogens. A pathogenetic hypothesis, proposing that regional tissue constraints act in concert with a peroxisomal-derived biochemical abnormality to impede centrosylvian neuronal migration, is discussed.

Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy.

The neuropathologic features of adrenomyeloneuropathy (AMN) are reviewed by supplementing those few previously published cases with 5 additional cases collected over the years. The endocrine involvement in AMN is briefly presented to serve as a pathogenetic backdrop and to emphasize that most of the lesions in AMN, as in adreno-leukodystrophy (ALD), are noninflammatory in the traditional sense of the word. The myeloneuropathy is emphasized, but the dysmyelinative/inflammatory demyelinative lesions also are presented. The preponderance of available data indicates that the myeloneuropathy of AMN is a central-peripheral distal (dying-back) axonopathy, as was originally proposed. The severity of the myeloneuropathy does not appear to correlate with the duration or severity of endocrine dysfunction. Microglia are the dominant participating cells in the noninflammatory myelopathy. Abnormalities in the ALD gene, which encodes a peroxisomal ABC half-transporter, do not correlate with clinical phenotypes. The relationship of the gene product, ALDP, to the peroxisomal very long chain fatty acid (VLCFA) synthetase, the activity of which is deficient in ALD/AMN, is unclear. An ALD-knockout mouse model has developed axonal degeneration, particularly in spinal cord, and is therefore more reminiscent of AMN than ALD. We continue to postulate that the fundamental defect in the myeloneuropathy of AMN is an axonal or neuronal membrane abnormality perhaps due to the incorporation of VLCFA-gangliosides, which perturbs the membrane's microenvironment and leads to dysfunction and atrophy.

An immunoperoxidase study of senile cerebral amyloidosis with pathogenetic considerations.

Samples of human cerebral cortex were obtained from twelve autopsied patients with Alzheimer's disease or "normal" aging. Rabbit or goat anti-human antisera to the following plasma proteins: IgG, F(ab')2, Fc, kappa and lambda light chains, IgM, IgA, fibrinogen, albumin, C3, lysozyme, haptoglobin, macroglobulin, and microglobulin; antibodies to the following intracellular proteins: glial fibrillary acidic (GFA) protein, filamin, actin, non-muscle myosin, tubulin, cholinergic vesicle proteins, and neurofilament (NF) proteins were utilized in the immunoglobulin peroxidase bridge. Amyloid cores of classical or perivascular plaques and dyshoric angiopathy exhibited a strong reaction for intact IgG and for both of its light chains, moderate reactions for lysozyme, fibrinogen, albumin and IgA, and weak reactions for IgM, C3, Fc, F(ab')2, haptoglobin, macroglobulin and microglobulin. Antibodies to all three NF proteins, individually and pooled, stained dyshoric and plaque amyloid, while antibodies to other intracellular proteins did not. The coronae of classical plaques and many primitive plaques stained for GFA, but inconsistently for IgG, both light chains, lysozyme, actin, tubulin, and NF proteins. Affected vessels of three patients with Congophilic angiopathy were reactive for all plasma proteins (especially IgG, fibrinogen, and albumin) and for NF proteins. NF staining in Congophilic blood vessels, although variable, revealed a peripheral or adventitial distribution, whereas plasma proteins tended to be localized in the media of the vessel wall. The distributions of Congo red and NF positivity were often identical. Both NF and Congo red staining was sensitive to oxidation. Isolated NF proteins were Congophilic and capable of displaying apple-green birefringence. A hypothesis concerning the role of NF proteins in senile cerebral amyloid is presented.

Retroperitoneal ganglioneuroblastoma: a kaleidoscope of neuronal degeneration. A light and electron microscopic study.

The light and electron microscopic features of an unique retroperitoneal ganglioneuroblastoma in a four-year-old female are described. The unprecedented concurrence of Hirano, zebra, membranous cytoplasmic (MCB), and Pick bodies in the same population of neoplastic, sympathetic ganglion cells provides further evidence for their non-specificity. Although the pathogenesis of the membranous cytoplasmic bodies in this tumor is unclear, they ostensibly arise within endoplasmic cisterns, similar to the proposed origin of membranous cytoplasmic bodies in Tay-Sachs disease. Both the apparent continuum between argyrophilic bodies and central chromatolysis, and the incorporation of various cytoplasmic constituents within neurofilamentous proliferations reflect some of the dynamic factors involved in the formation of Pick bodies.

Potential environmental and host participants in the early white matter lesion of adreno-leukodystrophy: morphologic evidence for CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1-mediated lipid antigen presentation.

The 2 most common forms of X-linked adreno-leukodystrophy (ALD) are the juvenile or childhood cerebral form with inflammatory demyelination and the adult adrenomyeloneuropathy (AMN) involving spinal cord tracts without significant inflammation. Modifier genes or environmental factors may contribute to the phenotypic variability. We performed immunohistochemical, an in situ polymerase chain reaction, and TUNEL analyses to identify several viruses, lymphocyte subpopulations, apoptotic cells, and effector molecules, focusing on morphologically normal white matter, dysmyelinative and acute demyelinative lesions. No distinguishing viral antigens were detected. Most lymphocytes were CD8 cytotoxic T cells (CTLs) with the alpha/beta TCR, and they infiltrated morphologically unaffected white matter. Only a few oligodendrocytes were immunoreactive for caspase-3. MHC class II- and TGF-beta-positive microglia were present. CD44, which can mediate MHC-unrestricted target cell death, was seen on many lymphocytes and white matter elements. CD1 molecules, which play major roles in MHC-unrestricted lipid antigen presentation, were noted. Our data indicate that unconventional CD8 CTLs are operative in the early stages of dysmyelination/demyelination and that cytolysis of oligodendrocytes, rather than apoptosis, appears to be the major mode of oligodendrocytic death. The presentation of lipid antigens may be a key pathogenetic element in ALD and AMN-ALD.

The dorsal root ganglia in adrenomyeloneuropathy: neuronal atrophy and abnormal mitochondria.

Adrenomyeloneuropathy (AMN), a disease of spinal cord, brain, adrenal, and testis, mostly affects men with spastic paraparesis or ataxia beginning in their second or third decade. The spinal cord displays bilateral, usually symmetrical, long tract degeneration particularly of the gracile tract in a "dying-back" pattern. The available data strongly indicate that the fundamental lesion in AMN is an axonopathy or neuronopathy. We compared lumbar dorsal root ganglia (DRG) from 3 AMN patients to 6 age-matched controls histologically, morphometrically, immunohistochemically, and ultrastructurally. There was no apparent neuronal loss, necrosis or apoptosis, nor obvious atrophy; nodules of Nageotte were sparse in both groups. The morphometric studies, however, did reveal neuronal atrophy with a decrease in the number of large neurons and a corresponding increase in neurons less than 2,000 microm2, especially in the 1,500-1,999 microm2 range. No consistent immunohistochemical differences were observed, and no specific cell type appeared to be lost. Many mitochondria in the AMN neurons demonstrated lipidic inclusions; this raises the possibility that, in addition to the well-known peroxisomal defect, impaired mitochondrial function may lead to a failure of ATP-dependent axoplasmic transport in AMN spinal tracts with consequent "dying-back" axonal degeneration. The observation that the DRG parent neurons of the degenerate gracile tracts in AMN undergo atrophy and do not display appreciable evidence of cell death, even at autopsy, provides a wide window of opportunity for the development of therapeutic strategies to combat or prevent this myeloneuropathy.

Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis.

Neurological dysfunction is a prominent feature of most peroxisomal disorders. Enormous progress in defining their gene defects has been achieved. The genes and gene products, peroxins (PEX), in five of the complementation groups have been defined. These studies confirm that Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) are a disease continuum. The gene defect in adreno-leukodystrophy (ALD) / adrenomyeloneuropathy (AMN) involves an integral peroxisomal membrane protein. Neuropathologic lesions are of three major classes: (i) abnormalities in neuronal migration or differentiation, (ii) defects in the formation or maintenance of central white matter, and (iii) postdevelopmental neuronal degenerations. The central white matter lesions are those of: (i) inflammatory demyelination, (ii) non-inflammatory dysmyelination, and (iii) non-specific reductions in myelin volume or staining with or without reactive astrocytosis. The neuronal degenerations are of two major types: (i) the axonopathy of AMN involving ascending and descending tracts of the spinal cord, and (ii) cerebellar atrophy in rhizomelic chondrodysplasia punctata and probably IRD. We postulate that the abnormal fatty acids in peroxisomal disorders, particularly very long chain fatty acids and phytanic acid, are incorporated into cell membranes and perturb their microenvironments resulting in dysfunction, atrophy and death of vulnerable cells. The advent of mouse models for ZS and ALD is anticipated to provide even greater pathogenetic insights into the peroxisomal disorders.

Adrenoleukodystrophy: molecular genetics, pathology, and Lorenzo's oil.

Knowledge about adrenoleukodystrophy (ALD), a disorder which was described first in 1923, has increased greatly during recent years. The principal biochemical abnormality, the presumed enzyme defect, and the gene defect, have been defined. A dietary therapy has been proposed and attracted world-wide attention through a motion picture. Nevertheless, many questions remain and cannot be answered without a more fundamental understanding of pathology and pathogenesis. This article will provide a review of the history, clinical features, pathology, biochemistry, and the gene defect, and then appraise current efforts to clarify pathogenesis and develop therapeutic approaches.

Diagnostic criteria for the neuropathologic assessment of Alzheimer's disease.

The provisional criteria proposed in 1985 by Khachaturian et al. emphasized numbers of plaques and neglected tangles, as did CERAD (Consortium to Establish a Registry for Alzheimer's Disease). The decision to set an arbitrary number of plaques as "pathologic" assumed that some neuritic plaques are a normal phenomenon in the aging brain. Neuritic plaques and neurofibrillary tangles are age-related lesions, but they are pathologic (i.e., lesions) no matter how many there are. In a clinically demented patient without vascular or other neurodegenerative lesions, a clinico-pathologic diagnosis of AD (a clinico-pathologic entity) can be made with a high level of confidence by demonstrating, and without counting, plaques and tangles. The vast majority of AD cases are straightforward, and diagnostic lesions can be appreciated with a simple silver stain. If patients' histories are unknown or uncertain, the clinical significance of the observed plaques and tangles must remain debatable. This is the essence of the consensus statement with which I wholeheartedly agree. In such cases without a dementia history, one can offer a neuropathologic diagnosis of Senile or Pre-senile Cerebral Disease (not "dementia") of the Alzheimer type. Precise clinico-pathologic correlations and some quantitative measures are needed for elucidating the pathogenesis of AD and for establishing a primary dementing diagnosis when AD is mixed with other dementing diseases. These correlations must be based on periodic and fairly extensive neuropsychological testing followed shortly thereafter by a detailed postmortem neuropathologic evaluation.

Pseudotumor cerebri due to partial obstruction of the sigmoid sinus by a cholesteatoma.

A 62-year-old man with pseudotumor cerebri (PTC) syndrome was discovered to have a cholesteatoma of the left mastoid. The mass indented the sigmoid sinus without occluding it. The PTC resolved postoperatively. To our knowledge, PTC has not been previously reported in association with a cholesteatoma. Additionally, this case demonstrated that a partial obstruction of the venous drainage of the brain may be sufficient to increase intracranial pressure.

Motor neuron disease and angiotropic lymphoma.

BACKGROUND: The number of patients with motor neuron disease (MND) and a concomitant hematologic disorder appears to be overrepresented. Angiotropic large cell lymphoma, a rare and aggressive type of lymphoma, has been associated with MND only once (to our knowledge) prior to this report. There are more than 35 cases of MND associated with lymphoma or monoclonal gammopathy reported in the literature. The nature of this association remains disputable. OBJECTIVE: To investigate whether the association between some MNDs and certain hematologic disorders is coincidental or pathogenetically related. CASE PRESENTATION: We describe the clinical and neuropathologic findings in a case involving a 70-year-old man with a rapidly progressive lower MND who at autopsy also exhibited angiotropic large cell lymphoma without ischemic lesions in the nervous system. CONCLUSIONS: This case supports the notion that the association between some MNDs and certain hematologic disorders is not coincidental but pathogenetically related. A 2-hit hypothesis is proposed in which an initial abnormal glycosylation in motoneurons would require the production of an appropriate autoantibody for disease expression.

Adrenoleukodystrophy. A clinical and pathological study of 17 cases.

Adrenoleukodystrophy was diagnosed pathologically in 17 male patients. The diagnosis was suggested by clinical and laboratory signs of primary adrenal failure and by neurological signs referable to the degeneration of white matter. Neurological findings usually predominated over clinical stigmata of adrenal failure. Adrenal biopsy has proved to be the most reliable diagnostic test, while brain biopsy has often been misleading. The histological picture of the brain lesion differs substantially from that of the adrenal, but the presence of similar ultrastructural cytoplasmic inclusions suggests a common metabolic disorder. Morphological analysis of the cerebral lesion indicates that the destruction may spread in a caudal-rostral direction. The intense inflammatory cell response occurs within the demyelinated areas, behing the area of active myelin breakdown, and appears to be a secondary feature of white matter degeneration.

Incorrect diagnosis of Alzheimer's disease. A clinicopathologic study.

OBJECTIVES: To examine the accuracy of clinical diagnoses of Alzheimer's disease (AD) in subjects enrolled in the Rochester Alzheimer's Disease Project (RADP) who were examined at autopsy, and to present a list of clinical "red flags." DESIGN: Autopsy examination of both prospective and retrospective subjects consecutively enrolled in this clinicopathologic study of the RADP. SETTING: University hospital and research center, using a multidisciplinary geriatric neurology clinic, satellite clinics, nursing home visits, and home visits. PATIENTS: One hundred seventy subjects clinically diagnosed as having AD who were enrolled in the RADP between 1983 and 1993 underwent neuropathologic examination. Of these, 93 had been enrolled prospectively and 77 retrospectively. MAIN OUTCOME MEASURES: Agreement between clinical and pathologic diagnoses. RESULTS: One hundred forty-nine subjects of 170 clinically diagnosed as having AD fulfilled the pathologic criteria for AD, yielding an accuracy rate of 88%. Of 93 subjects enrolled prospectively and diagnosed as having AD, 83 (90%) met the histologic criteria for AD. Of the 77 subjects enrolled retrospectively, neuropathologic examination indicated definite AD in 66 (86%). CONCLUSIONS: There was a high correlation between clinicians' diagnoses and final pathologic diagnoses. The most common clinical errors involved the misdiagnosis of dementias due to Parkinson's disease and cerebrovascular disease. There was no significant difference in the accuracy rates of subjects enrolled prospectively and retrospectively.