The neuropathology of chromosome 17-linked dementia.

We recently described a family with chromosome 17-linked dementia, characterized clinically by disinhibition-dementia-parkinsonism-amyotrophy complex. We report now the neuropathology of 6 affected family members. This included semiquantitative scoring of neuronal loss, gliosis, and spongiosis and immunocytochemical and ultrastructural characterization of neuronal and glial inclusions. The changes consisted of circumscribed neuronal loss, gliosis, and spongiosis of limbic neocortical areas and frontal, temporal, and occipital association areas. Similar changes were present in subcortical nuclei, most severe in the substantia nigra, but also involved the ventral striatum and amygdala. The hippocampus was spared except for degeneration of the afferent perforant tract, secondary to entorhinal nerve cell loss. Argyrophilic neuronal inclusions, with a characteristic immunocytochemical profile, were found in brainstem nuclei, hypothalamus and basal ganglia. Ultrastructurally, in 3 patients these inclusions showed hitherto undescribed abnormally assembled filaments. Glial cytoplasmic inclusions were widespread in white matter structures. Immunocytochemistry failed to demonstrate the protease-resistant prion protein. The pathology appears to be unique, involving various cortical and subcortical structures, and is consistent with the clinical findings of Kluver-Bucy-like syndrome, parkinsonism, and frontal lobe dementia. For this entity we suggest the term "chromosome 17-linked dementia."

Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex.

We studied the clinical features, pathology, and molecular genetics of a family (Mo) with an autosomal dominant disinhibition, frontal lobe dementia, parkinsonism, and amyotrophy. We examined seven affected members and gathered clinical information on another six. The mean onset was at age 45 years. Personality and behavioral changes (disinhibition, withdrawal, alcoholism, hyperphagia) were the first symptoms in twelve. There was early memory loss, anomia, and poor construction with preservation until late of orientation, speech, and calculations. All affected members examined had rigidity, bradykinesia, and postural instability. Mean duration to death was 13 years. We studied the neuropathology of six individuals, five of whom had been examined in life. There was atrophy and spongiform change in the frontotemporal cortex, and neuronal loss and gliosis in the substantia nigra and amygdala. Two individuals, including one with fasciculations and muscle wasting, had anterior horn cell loss. There were no Lewy bodies, neurofibrillary tangles, or amyloid plaques. We call this disorder the "disinhibition-dementia-parkinsonism-amyotrophy complex" (DDPAC), based on the clinical syndrome found in this family and linkage to chromosome 17.

Enterogenous cyst of the orbital apex and superior orbital fissure.

BACKGROUND: Enterogenous cysts of the central nervous system are rare congenital tumors with a single layer of mucin-secreting epithelial cells resembling gastrointestinal epithelium. The tumor is located most commonly at lower cervical and cervicothoracic spinal levels; only 22 intracranial cases have been reported. To the authors knowledge, this entity has not been described in the orbit. METHODS: A 23-year-old woman with painful loss of vision and ophthalmoplegia in the left eye was treated with oral and intravenous corticosteroids for presumed orbital inflammation. After a cystic lesion in the left orbital apex was demonstrated on computed tomographic scan and magnetic resonance imaging, various diagnoses, including optic nerve tumor, granulomatous inflammation, lymphoma, vascular anomaly, and pseudotumor, were considered until transcranial biopsy established the correct diagnosis. The tumor subsequently recurred twice. RESULTS: More than 3 years after the last recurrence, the patient has no pain but had unilateral optic atrophy, significant visual field loss, limited motility, and an anesthetic cornea in the left eye. CONCLUSION: The diagnosis of enterogenous cyst is difficult without adequate biopsy because the radiologic and clinical presentation of this rare tumor may be confused with other lesions. Previous attempts to explain intracranially placed enterogenous cysts offer no explanation for an orbital occurrence nor do they adequately describe a mechanism for an intracranial location in general. An embryologically based explanation that takes into account the occurrence of this entity from the caudal to rostral extent of the neuraxis is described. This theory suggests that the orbit is the most rostral possible location for an enterogenous cyst.

Sexual dimorphism of the human corpus callosum from three independent samples: relative size of the corpus callosum.

Three independent autopsy samples of brains without apparent neuropathology were studied to ascertain whether there was sexual dimorphism in the human corpus callosum (CC). Using planimetric measurements on midsagittal brain sections, several morphometric features of the CC were studied: total callosal area, maximum dorsoventral splenial width, the posterior one fifth of the total area of the CC (mostly splenium), and brain weight. Ratio data correcting for brain size were also studied. In all samples, absolute brain size was larger in males, and significantly so. Measurements of splenial dorsoventral width were higher in females than males, but not significantly, except in the Australian sample. Total callosal area was absolutely higher in the Australian female sample than in males, and almost equal in the two American samples, without statistically significant differences. The posterior one-fifth area (splenium) was larger for females in each of the samples. The variables which were corrected for brain size were usually significantly larger in females, although this pattern varied in each sample. The statistical pattern of sexual dimorphism for the human CC differs from that found in most other neural structures, such as the amygdaloid nucleus, cerebellum, hippocampus, and thalamus. The absolute sizes of these structures are always significantly larger in males. When corrected for brain size, the relative sizes are not significantly larger. The CC is the only structure to show a larger set of relative measures in females.

Melas: an original case and clinical criteria for diagnosis.

We describe the full history and postmortem findings in one of the first identified cases of mitochondrial encephalomyopathy with stroke-like episodes (MELAS). To clarify diagnostic criteria, we analyzed 69 reported cases. The syndrome should be suspected by the following three invariant criteria: (1) stroke-like episode before age 40 yr; (2) encephalopathy characterized by seizures, dementia, or both; and (3) lactic acidosis, ragged-red fibers (RRF), or both. The diagnosis may be considered secure if there are also at least two of the following: normal early development, recurrent headache, or recurrent vomiting. There are incomplete syndromes in relatives of patients with the full syndrome and incomplete syndromes might also be encountered in sporadic cases. Some MELAS patients have features of the Kearns-Sayre syndrome (KSS) or myoclonic epilepsy with ragged-red fibers (MERRF), but none had the full KSS syndrome. In partial or confusing cases, analysis of mitochondrial DNA (mtDNA) may point to the correct diagnosis; however, not all patients with clinical MELAS have had the typical mtDNA point mutation and some patients with the mutation have clinical syndromes other than MELAS.

Study of movement disorders and brain iron by MR.

Heavily T2-weighted high-field MR images provide a unique opportunity for the evaluation of the extrapyramidal motor system. The images are affected by the presence of small amounts of naturally occurring paramagnetic substances--principally iron--that delineate the neostriatum (caudate and putamen), globus pallidus, red nucleus, substantia nigra, and dentate nucleus, primarily by a decrease in signal secondary to the T2* effect. Movement disorders are associated with either increased or decreased signal or both in these structures, depending on the pathologic process. In the initial evaluation of 113 patients with a variety of movement disorders, good correlation of imaging abnormalities can be made with a simplified schema of the extrapyramidal pathways and a system of classification of abnormal movements, parkinsonism/tremor, dystonia, chorea, myoclonus, and hemiballismus. Parkinsonisms are characterized by abnormalities of the cortico-ponto-cerebello-dentato-rubro-thalamo-cortico-spinal tract or the nigrostriatal tract. Dystonias are characterized by abnormalities of the neostriatum predominantly affecting the putamen. Choreas are also characterized by abnormalities of the neostriatum but predominantly affecting the caudate nucleus. Hemiballismus is characterized by lesions affecting the subthalamic nucleus or associated pathway.

Chronic syndrome of inappropriate antidiuretic hormone secretion and hypertension in a patient with olfactory neuroblastoma. Evidence of ectopic production of arginine vasopressin by the tumor.

A 28-year-old man with the chronic syndrome of Inappropriate antidiuretic hormone secretion and hypertension was found to have an olfactory neuroblastoma. We demonstrated evidence of elevated circulating arginine vasopressin levels, significantly elevated arginine vasopressin and vasopressin neurophysin levels in the tumor extract, and immunohistochemical staining for arginine vasopressin and vasopressin neurophysin in the tumor cells. The patient's clinical syndrome, including hypertension, resolved following subtotal removal of the tumor and radiation therapy. This study identified olfactory neuroblastoma as a definite cause of ectopic arginine vasopressin secretion causing the syndrome of inappropriate antidiuretic hormone secretion.

Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyzes the formation of mevalonate, an essential precursor for isoprenoid compounds in mammalian cells. Recent studies have shown that mevinolin, a competitive inhibitor of the reductase, inhibits cell proliferation and induces differentiation in cultured C1300 (Neuro-2A) murine neuroblastoma cells. We now report that mevinolin can inhibit neuroblastoma growth in vivo. The specific activity of HMG-CoA reductase in subcutaneous neuroblastomas increased more than 20-fold between the fifth and eighth days after tumor inoculation, and remained elevated for the remainder of the tumor lifetime in mice. The increase in reductase activity was correlated with a marked increase in tumor DNA content and exponential increase in tumor weight. Using an in vitro assay to monitor the ability of mouse serum to suppress sterol synthesis, we determined that mevinolin was inactivated or cleared from the circulation within 3-6 h after a single subcutaneous injection. However, by using subcutaneous osmotic pumps to deliver a constant infusion of mevinolin, we were able to maintain adequate blood levels of the drug for 7 d. Mevinolin (5 mg/kg per h) suppressed tumor growth (wet weight) significantly when treatment was carried out between day 1 and day 8 or between day 5 and day 12 after tumor inoculation. Histopathological examination of tumors from mevinolin-treated mice revealed few or no mitotic figures and marked cellular degeneration. Measurements of incorporation of (3H)acetate into neuroblastoma sterols and ubiquinones 24 h after implantation of osmotic pumps showed that mevinolin produced a marked inhibition of isoprenoid synthesis in the tumors in vivo. The data suggest that, in addition to their demonstrated utility as cholesterol-lowering drugs, competitive inhibitors of HMG-CoA reductase may have considerable potential as novel antineoplastic agents.

Neutral metalloendopeptidase in human male genital tract. Comparison to angiotensin I-converting enzyme.

High concentrations of neutral metalloendopeptidase (NEP) (enkephalinase) were found in human male genital tract immunohistochemically and by enzyme activity assays, and its distribution was compared with that of angiotensin-converting enzyme (ACE) (kininase II). Whereas the two enzymes colocalize on the luminal aspect of proximal tubular epithelium and are not found elsewhere in the nephron, their distribution in the male genitalia is different. Seminal fluid is rich in NEP and ACE, but after ultracentrifugation ACE remains soluble while NEP sediments. NEP activity is low in testicular homogenate but high in the particulate fraction of epididymides and prostates. ACE, on the other hand, is active in the particulate fraction of testes and in the soluble fraction of epididymides and prostates. Prostatic NEP had a slightly higher molecular weight than the renal NEP, which was reduced by neuraminidase in electroblotting. Testicular and seminal plasma ACE also had a slightly higher molecular weight than the purified renal enzyme (150,000), probably caused by removal of an "anchor" peptide during purification. In the prostate, NEP was found by three different immunohistochemical techniques in luminal epithelial cells and in lumina. The function of NEP in the genital tract may be related to sperm maturation and proacrosin activation.

Angiotensin-converting enzyme in epithelial and neuroepithelial cells.

Angiotensin-converting enzyme (CE) occurs in three types of cell: endothelial, epithelial, and neuroepithelial. In all three, it appears to be bound to plasma membrane. With antisera to the human enzyme, CE is demonstrated in paraffin sections on the apical surface of epithelial cells in the proximal tubule of the kidney, the mucosa of the small intestine, the syncytial trophoblast of the placenta, and the choroid plexus. Epithelial CE is characteristically found on microvillous surfaces in contact with an effluent, well placed to act on substrate in flux. In the brain, CE occurs in nerve fibers and terminals, mainly mesiobasally and in basal ganglia. Mesiobasal CE coincides with other components of the renin-angiotensin system (RAS) in the choroid/ventricular fluid, the subfornical organ, and the magnocellular neurosecretory system of the hypothalamus. Extrapyramidal CE, however, may not be related to the RAS. In the substantia nigra and the globus pallidus, the enzyme has the same cellular distribution as two putative neuromodulators, substance P and enkephalin, the latter a known substrate of CE.

Macroglobulinemia with peripheral neuropathy simulating motor neuron disease.

A 48-year-old man with an IgM plasma cell dyscrasia died after 14 months of symptoms and signs typical of motor neuron disease, including widespread fasciculation and normal sensation. Two laboratory results were atypical: cerebrospinal fluid protein content of 132 mg/dl and slow motor nerve conduction. At autopsy, no loss or atrophy of anterior horn neurons was found; instead, degeneration of ventral and dorsal roots and retrograde changes of chromatolysis in motor neurons implied peripheral neuropathy. Most reported cases of neuropathy associated with plasma cell dyscrasias have been sensorimotor or purely sensory, but there have been 14 previous cases of motor disorders.

Hydrolysis of enkephalins by human converting enzyme and localization of the enzyme in neuronal components of the brain.

Homogeneous human CE hydrolyzed Met5-enkephalin fastest of the biologically active substrates tested. The inactivation of Met5-enkephalin was inhibited by antiserum to Ce and by specific inhibitor of CE (MK 421; I50 = 8 x 10(-9)M). Direct radioimmunoassay of CE extracted from basal ganglia indicated immunological identity of lung, kidney, and brain CE. Immunocytochemically, CE was demonstrated in the choroid plexus, where the enzyme appears to be bound, as in kidney and gut, to the surface of the epithelial cell bathed by luminal fluid. CE immunoreactivity in brain parenchyma was demonstrated in neuronal elements in the hippocampus, hypothalamus, neocortex, globus pallidus, and substantia nigra.

Wide distribution of immunoreactive renin in nerve cells of human brain.

By use of the indirect peroxidase-antiperoxidase complex immunocytochemical technique, antibody to purified human renal renin was applied to formalin-fixed paraffin sections of human cadaver brain. Immune reaction products were observed in most nerve cells in all areas of the brain examined; staining was limited to the soma and proximal dendrites. These experiments have confirmed the presence of a renin-like substance in central nervous tissue and suggest a more generalized function for "brain renin" than was previously anticipated.