The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes.

Type 2 diabetes is a polygenic and genetically heterogeneous disease . The age of onset of the disease is usually late and environmental factors may be required to induce the complete diabetic phenotype. Susceptibility genes for diabetes have not yet been identified. Islet-brain-1 (IB1, encoded by MAPK8IP1), a novel DNA-binding transactivator of the glucose transporter GLUT2 (encoded by SLC2A2), is the homologue of the c-Jun amino-terminal kinase-interacting protein-1 (JIP-1; refs 2-5). We evaluated the role of IBi in beta-cells by expression of a MAPK8IP1 antisense RNA in a stable insulinoma beta-cell line. A 38% decrease in IB1 protein content resulted in a 49% and a 41% reduction in SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, we detected MAPK8IP1 transcripts and IBi protein in human pancreatic islets. These data establish MAPK8IP1 as a candidate gene for human diabetes. Sibpair analyses performed on i49 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. We did, however, identify in one family a missense mutation located in the coding region of MAPK8IP1 (559N) that segregated with diabetes. In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of 3-cell function.

The long-distance effects of brain lesions: visualization of myelinated pathways in the human brain using polarizing and fluorescence microscopy.

We describe several new possibilities for the study of degenerated myelinated tracts in the human central nervous system (CNS). The methods are based on the visualization of myelin breakdown products that show birefringence in polarized light and, when stained with Nile blue and benzpyrene-3,4, exhibit fluorescence. Even after lengthy formalin fixation, the methods permit the localization of anterogradely degenerated tracts in a variety of fiber systems in the brains of patients who died between five and 20 months after the onset of neurological symptoms. Particularly the polarizing technique, because of its simplicity, can be added to the usual neuropathological methods for demonstrating the long-distance effects of a brain lesion. As research tools, these methods would also aid in the study of the anatomical substrate of human neurological symptomatology.

The long distance effects of brain lesions: visualization of axonal pathways and their terminations in the human brain by the Nauta method.

This study aims at determining the reliability and the optimal post-injury survival time for the application of the Nauta technique to the analysis of the human brain. The Nauta method reveals the degeneration not only of nerve fibers, myelinated and unmyelinated, but also of their terminations. Immunohistochemical and ultrastructural observations appear to prove that the Nauta technique indeed stains axons in human autopsy material. The optimal survival time for the use of the Nauta method was found to be between nine days and five months. In cases with longer survival times--up to 20 months--the Nauta technique and a previously proposed polarizing technique (showing birefringent breakdown products of myelin) can be used as complementary methods. Applying these techniques to the human brain may help define the anatomical basis of neurological and neuropsychological symptoms important for man.

Alzheimer disease: curly fibers and tangles in organs other than brain.

The filamentous brain lesions that define Alzheimer disease (AD) consist of senile plaques and neurofibrillary tangles. Undulated pathological filaments--curly fibers or neuropil threads--also occur in the neuropil. Beta-amyloid precursor proteins are synthesized by many cells outside the central nervous system and recently, deposition of beta-amyloid-protein was reported to occur in non-neuronal tissues. In addition, increasing data claim the importance of chronic inflammation in the pathogenesis of AD. These observations suggest that AD may be a widespread systemic disorder. Here we report that pathological argyrophilic filaments with histochemical properties of amyloid showing striking morphological similarity to curly fibers and/or tangles accumulate not only in ependymal layer and in epithelial cells of choroid plexus, but also in several other organs (e.g. liver, pancreas, ovary, testis, thyroid) in AD. The ependyma, choroid plexus, and various organs of 39 autopsy cases were analyzed. In search of curly fiber and tangle-like changes in organs other than brain, 395 blocks from 21 different tissues of 24 AD cases, 5 cases with discrete or moderate AD-type changes, and 10 control cases were investigated. We found in non-neuronal cells "curly fibers" or "tangles" immunoreactive with antibodies to P component, Tau-protein, ubiquitin, fibronectin, and Apolipoprotein-E, but lacking immunoreactivity with antibodies to neurofilament proteins. Ultrastructurally they consist of densely packed straight and paired helical filaments and closely resemble neurofibrillary tangles and neuropil threads. These observations indicate that the formation of "curly fibers" and "tangles" is not unique to the central nervous system. The results suggest that AD might be a systemic disorder or that similar fibrillary changes to tangles and curly fibers may also be associated with other amyloidosis than beta-amyloidosis. Further investigations are necessary to understand the pathogenetic interest of these fibrillary changes outside the CNS.

Primary motor cortex involvement in Alzheimer disease.

In Alzheimer disease (AD) the involvement of entorhinal cortex, hippocampus, and associative cortical areas is well established. Regarding the involvement of the primary motor cortex the reported data are contradictory. In order to determine whether the primary motor cortex is involved in AD, the brains of 29 autopsy cases were studied, including, 17 cases with severe cortical AD-type changes with definite diagnoses of AD, 7 age-matched cases with discrete to moderate cortical AD-type changes, and 5 control cases without any AD-type cortical changes. Morphometric analysis of the cortical surface occupied by senile plaques (SPs) on beta-amyloid-immunostained sections and quantitative analysis of neurofibrillary tangles (NFTs) on Gallyas-stained sections was performed in 5 different cortical areas including the primary motor cortex. The percentage of cortical surface occupied by SPs was similar in all cortical areas, without significant difference and corresponded to 16.7% in entorhinal cortex, 21.3% in frontal associative, 16% in parietal associative, and 15.8% in primary motor cortex. The number of NFTs in the entorhinal cortex was significantly higher (41 per 0.4 mm2), compared with those in other cortical areas (20.5 in frontal, 17.9 in parietal and 11.5 in the primary motor cortex). Our findings indicate that the primary motor cortex is significantly involved in AD and suggest the appearance of motor dysfunction in late and terminal stages of the disease.

Curly fiber and tangle-like inclusions in the ependyma and choroid plexus--a pathogenetic relationship with the cortical Alzheimer-type changes?

The question of whether thread- and tangle-like inclusions of the choroid plexus (known as Biondi inclusions) are related to the cortical lesions in Alzheimer disease (AD) has been debated for almost a century, yet remains unanswered. Recently beta-amyloid protein was biochemically isolated from the plexus, indicating a possible pathogenetic relationship between the degenerative changes of the cerebral cortex and those of the plexus. The goal of the present study was to analyze whether or not a significant correlation exists between the occurrence of the cortical AD-type changes and those in the ependyma and choroid plexus. In 292 consecutive autopsy cases several cortical areas, the ependyma, and the choroid plexus were analyzed to look for AD-type changes and Biondi inclusions using histochemical staining techniques and immunohistochemistry. A semiquantitative analysis of the density of cortical AD-type changes showed that of the 292 cases, 63 had severe cortical changes, 23 moderate changes, and 142 discrete changes. In 64 cases no plaques or neurofibrillary tangles were found. The number of cases with thread- and tangle-like elements in the plexus and ependyma was more than 96% in the 3 groups with cortical AD-type lesions, but low in the group without AD-type cortical changes (19%). The pathological argyrophilic filaments accumulating in the ependymal layer and plexus had histochemical properties of amyloid and were immunoreactive with antibodies to P component, ubiquitin, fibronectin and Tau protein. They did not react with antibodies to neurofilament proteins. Ultrastructurally, they consisted of densely packed straight and paired helical filaments and closely resembled neurofibrillary tangles and neuropil threads. The highly significant correlation (chi2, p = 0.001; R = 0.85) between the occurrence of AD-type changes in the cortex and those in ependyma and plexus suggests a pathogenetic relationship.

Occipital cortex in man: organization of callosal connections, related myelo- and cytoarchitecture, and putative boundaries of functional visual areas.

Human area 17 is known to contain a single (the primary) visual area, whereas areas 18 and 19 are believed to contain multiple visual areas (defined as individual representations of the contralateral visual hemifield). This is known to be the case in monkeys, where several boundaries between visual areas are characterized by bands of callosal afferents and/or by changes in myeloarchitecture. We here describe the pattern of callosal afferents in (human) areas 17, 18, and 19 as well as their cortical architecture and we infer the position of some visual areas. Sections from occipital lobes of 6 human brains with unilateral occipital infarctions have been silver-impregnated for degenerating axons, thereby revealing callosal afferents to the intact occipital cortex. Their tangential distribution is discontinuous, even in cases with large lesions. A band of callosal afferents straddles the area 17/18 boundary, whereas the remainder of area 17 and a 15-45 mm wide stripe of area 18 adjacent to the callosal band along the 17/18 border are free of them. Patches of callosal afferents alternate with callosal-free regions more laterally in area 18 and in area 19. We conclude that, in man, a second visual area (analogue of V2) lies in area 18, horseshoe-shaped around area 17, and includes the inner part of the acallosal stripe adjacent to the callosal band along the 17/18 boundary. The outer part of this acallosal stripe belongs to a third visual area, which may contain dorsally the analogue of V3 and ventrally that of VP. Thus the lower parts of the second and third visual areas lie on the lingual gyrus, whereas the analogue of the macaque's fourth visual area probably lies on the fusiform gyrus. Although the proposed subdivision of the occipital cortex relies largely on the pattern of callosal afferents, some putative human visual areas appear to have distinct architectonic features. The analogue of V2 is rather heavily myelinated and its layer III contains large pyramidal neurons. Its upper part is not well delimited laterally since adjacent "V" has similar architecture. Its lower part, however, differs clearly from the adjacent "VP," which is lightly myelinated and lacks the large pyramids in layer III. The cortex lateral to "VP" is heavily myelinated and contains fairly large pyramids in layers III and V. The myeloarchitecture of the lateral part of the occipital cortex is not uniform; a very heavily myelinated region stands out in the lateral part of area 19, near the occipito-temporal junction.(ABSTRACT TRUNCATED AT 400 WORDS)

Borrelia rhombencephalomyelopathy.

Three patients, in whom the diagnosis of Borrelia burgdorferi infection was unknown for several years, developed a biphasic involvement of the central nervous system: an acute brain-stem dysfunction was followed up, in two patients, by a progressive, disabling myelitis and, in one patient, by further relapsing-remitting episodes of severe multifocal rhombencephalitis. The most consistent cerebrospinal fluid abnormalities in the analysis of sequential specimens were elevated total IgM levels that normalized after penicillin therapy. The neuropathologic findings in one patient showed microgliosis and meningovascular involvement of the central nervous system, resulting in two ischemic infarcts in the myelencephalon. Few spirochetes were localized in the leptomeninges and around subependymal vessels of the fourth ventricle. The vascular element consisted of an obliterative inflammatory vasculopathy in the medullary parenchyma. This study (1) provides pathologic evidence that a vascular disease induced by B burgdorferi is a pathogenetic mechanism for cerebrovascular diseases, and (2) emphasizes the similarities between neuroborreliosis and neurosyphilis.

Postanoxic generalized dystonia improved by bilateral Voa thalamic deep brain stimulation.

A patient with severe postanoxic dystonia and bilateral necrosis of the basal ganglia, who was confined to a wheelchair, underwent bilateral ventralis oralis anterior deep brain stimulation (Voa-DBS) after 6 weeks of unsuccessful bilateral pallidal DBS (GPi-DBS). After 4 months of high intensity Voa-DBS, cognitively unimpaired, he showed major improvement in dystonia, became ambulant, but committed suicide. Brain examination confirmed the correct location of the electrodes in GPi and Voa on both sides.

Alzheimer's disease--a spirochetosis?

The aetiology of Alzheimer's disease (AD), which affects a large proportion of the aged population is unknown and the treatment unresolved. The role of beta amyloid protein (beta A4), derived from a larger amyloid precursor protein (APP) in AD is the subject of intense research. Here I report observations that in 14 autopsy cases with histopathologically confirmed AD, spirochetes were found in blood and cerebrospinal fluid and, moreover, could be isolated from brain tissue. Thirteen age-matched control cases were without spirochetes. Reference strains of spirochetes and those isolated from brains of AD patients, showed positive immunoreaction with monoclonal antibody against the beta amyloid precursor protein. These observations suggest that spirochetes may be one of the causes of AD and that they may be the source of the beta amyloid deposited in the AD brain.

Further ultrastructural evidence that spirochaetes may play a role in the aetiology of Alzheimer's disease.

Recently it was reported that, at autopsy, in neuropathologically confirmed cases of Alzheimer's disease spirochaetes were found in blood and cerebrospinal fluid using dark-field microscopy. Moreover, the spirochaetes were isolated and cultured from brain tissue. We now show, using scanning electron microscopy and atomic force microscopy that the helically shaped microorganisms isolated and cultured from the Alzheimer brains possess axial filaments. This indicates that these microorganisms taxonomically indeed belong to the order Spirochaetales. A morphometric analysis reinforces this notion.

Cholesterol ester crystals in polarized light show pathways in the human brain.

It is well known that crystals of cholesterol esters exhibit birefringence. In the central nervous system such crystals are formed in the course of myelin degeneration following axonal interruption. Thus, anterogradely degenerated tracts assume birefringence. In the human brain, where modern tracing techniques commonly used in animals cannot be applied, anterogradely degenerated fiber systems can be visualized in formalin-fixed frozen tissue by simple polarizing microscopy. Using this phenomenon, tracing cerebral connections may permit one to interpret neuropsychological symptoms unique to man (aphasia, amnesia, neglect). Also, it should be a useful addition to routine neuropathology for it shows the long-distance effects of a brain lesion; it would facilitate the study of peripheral nerve pathology; and it would yield information about the age of a lesion.

Early symptoms and outcome of Listeria monocytogenes rhombencephalitis: 14 adult cases.

Listeria monocytogenes rhombencephalitis has never been studied in a significant group of patients. We describe 14 adult cases who were seen over a 10-year period. A biphasic illness was characteristic: (1) prodromes (5-15 days) with malaise, fatigue, headache, nausea or vomiting, and fever; (2) cranial nerve palsy with facial palsy, diplopia, dysphagia, dysarthria, usually multiple. Meningism and hemi- or tetraparesis were present in 11 patients and cerebellar dysfunction in 9 patients. In 4 cases, CT showed widening of the brain stem with disappearance of the surrounding cisterns. The cerebrospinal fluid was abnormal in all patients in whom this investigation was done (pleocytosis, elevation in protein content). The patients received antibiotic therapy for 2-6 weeks. In the 9 patients who recovered, the neurological dysfunction improved within 2 days to 1 week of the initiation of therapy. There were 5 deaths. At autopsy in 2 cases, there was severe purulent meningitis and rhombencephalitis with predominantly polymorphonuclear cellular infiltration in 1 case, while numerous microabscesses in the midbrain, pons and medulla were observed in the other. We conclude that L. monocytogenes infection should be considered in patients who develop fever and focal neurological signs particularly localized to the brain stem.

A CADASIL case with normal skin biopsy and without mutations in exons 3 and 4 of the Notch3 gene.

The diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is usually confirmed by genetic testing or skin biopsy. We here report the case of a 69-year-old woman with recurrent transient ischemic attacks (TIAs) and strokes, seizures, and dementia without any mutations in exons 3 and 4 of the Notch3 gene and with a normal skin biopsy, but who showed characteristic CADASIL abnormalities on brain pathological examination. Our findings suggest that negative results in these two tests do not exclude the disease and a leptomeningeal biopsy or a second skin biopsy should be considered in such cases.

Early olfactory involvement in Alzheimer's disease.

BACKGROUND: In Alzheimer's disease (AD) the olfactory system, including the olfactory bulb, a limbic paleocortex is severely damaged. The occurrence of early olfactory deficits and the presence of senile plaques and neurofibrillary tangles in olfactory bulb were reported previously by a few authors. The goal of the present study was to analyze the occurrence of AD-type degenerative changes in the peripheral part of the olfactory system and to answer the question whether the frequency and severity of changes in the olfactory bulb and tract are associated with those of the cerebral cortex in AD. MATERIAL AND METHODS: In 110 autopsy cases several cortical areas and the olfactory bulb and tract were analyzed using histo- and immunohistochemical techniques. Based on a semiquantitative analysis of cortical senile plaques, neurofibrillary tangles and curly fibers, the 110 cases were divided into four groups: 19 cases with severe (definite AD), 14 cases with moderate, 58 cases with discrete and 19 control cases without AD-type cortical changes. RESULTS: The number of cases with olfactory involvement was very high, more than 84% in the three groups with cortical AD-type lesions. Degenerative olfactory changes were present in all 19 definite AD cases, and in two of the 19 controls. The statistical analysis showed a significant association between the peripheral olfactory and cortical degenerative changes with respect to their frequency and severity (P < 0.001). Neurofibrillary tangles and neuropil threads appear in the olfactory system as early as in entorhinal cortex. CONCLUSION: The results indicate a close relationship between the olfactory and cortical degenerative changes and indicate that the involvement of the olfactory bulb and tract is one of the earliest events in the degenerative process of the central nervous system in AD.

[Nervous system pathology in AIDS: results of a collaborative autopsy study from Switzerland]. / Pathologie des zentralen Nerven-systems bei Aids: Resultate einer kollaborativen Autopsiestudie aus der Schweiz.

Neuropathological lesions were studied in a consecutive autopsy series of 206 cases, comprising 61% of all patients who died of Aids in Switzerland between April 1981 and December 1988. Central nervous system involvement was found in 84% of the patients, and 17% showed multiple concomitant intracerebral lesions. Among the non-viral opportunistic infections, cerebral toxoplasmosis was most frequent (24%), whilst among the viral opportunistic infections, cytomegalovirus (CMV) encephalitis was most frequent (7%). A nodular encephalitis consisting of disseminated microglial nodules without morphological or immunocytochemical evidence of CMV occurred in 13.5% of the patients. The majority of these cases showed evidence of extracerebral CMV infection. Progressive multifocal leukoencephalopathy (PML) was observed in 6% of the patients and was associated with widespread tissue destruction and cyst formation. HIV encephalopathy occurred in 38 patients (18%) and showed two characteristic morphological patterns: progressive diffuse leukoencephalopathy (PDL) and multifocal giant cell encephalitis (MGCE). PDL was observed in 22 patients and was characterized by a diffuse demyelination and gliosis of the white matter with little inflammatory infiltrates and scattered multinucleated giant cells which were immunoreactive to HIV antigens. MGCE was found in 16 patients and was characterized by clusters of macrophages, lymphocytes, and HIV-immunoreactive multi-nucleated giant cells. In our view, PDL and MGCE represent two opposite variants of HIV-induced encephalopathies with numerous intermediate manifestations.

Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys.

It has been established that neuroinflammation is present in the substantia nigra (SN) of Parkinson disease (PD) cases but the factors responsible are as yet unknown. One contributing protein may be the intercellular adhesion molecule-1 (ICAM-1, CD54). ICAM-1 with its counter receptor, the lymphocyte function-associated antigen 1 (LFA-1) is known to play a key role in inflammatory processes and in T-cell mediated host defense mechanisms. We detected large numbers of ICAM-1-positive reactive astrocytes in the SN of a series of 14 patients with neuropathologically confirmed PD, including 3 of familial origin, compared with 11 age-matched controls. In PD SN, these ICAM-1-positive reactive astrocytes were particularly concentrated around many residual neurons in areas of heavy neuronal loss and extracellular melanin accumulation. LFA-1-positive reactive microglia gathered in areas of intense ICAM-1 expression, and LFA-1-positive leukocytes were identified infiltrating the tissue. Double immunostaining for ICAM-1 and LFA-1 revealed aggregates of reactive microglia embedded in areas of diffuse ICAM-1. Leukocyte counts were 5 fold higher in PD SN compared to controls (P < 0.001). Similar over-expression of ICAM-1 was found in monkeys that had been exposed to MPTP from 5.5 to 14 years previously compared with control monkeys. The presence of ICAM-1-positive reactive astrocytes in Parkinson disease and MPTP-treated monkeys is indicative of a sustained inflammatory process and suggests that antiinflammatory agents may have a place in PD therapy.