Hippocampal cavities are not associated with cognitive impairment in transient global amnesia.

BACKGROUND: Hippocampal sulcal cavities (HSC) have been speculated to contribute to a higher vulnerability of memory pathways and might be a possible etiological factor in transient global amnesia (TGA). Therefore, we evaluated the influence of HSC on cognitive long-term outcome in TGA-patients. METHODS: Fourteen otherwise healthy patients with the clinical syndrome of TGA in their history underwent a high-resolution magnetic resolution imaging and a comprehensive neuropsychological test battery. The neuropsychological control group consisted of 15 healthy subjects and was balanced for age, sex and other risk factors as well as intellectual and social status. RESULTS: Magnetic resolution imaging and neuropsychological testing have been performed 1128 days (median) after the TGA. HSC have been detected in nine of the 14 patients and have been bilateral in eight of them. There were no differences in cognitive performance in patients with and without HSC as well as compared to healthy subjects. Even in patients with greater lesion load, only a slight visuospatial deficit was found. CONCLUSIONS: Although an increased incidence of HSCs is detected in TGA patients, cavities are not obligatorily in TGA. Moreover, even patients with hippocampal cavities achieve a full neuropsychological recovery independent of the frequency and size of the hippocampal lesions.

Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.

Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.

Early diagnosis of rhinocerebral mucormycosis by cerebrospinal fluid analysis and determination of 16s rRNA gene sequence.

A 40-year-old diabetic woman was diagnosed with rhinocerebral mucormycosis. Cerebral mucormycosis is an acute life-threatening disease, which is caused by fungi of the class Phycomycetae. Clinical suspicion and detection of the fungal hyphae in cerebrospinal fluid (CSF) led to early diagnosis, subsequently confirmed by immunohistochemistry and molecular analysis of fungal RNA. Early infiltration of the infectious agent into the central nervous system resulted in septic thrombosis of the cavernous sinus, mycotic meningoencephalitis, brain infarctions as well as intracerebral and subarachnoidal hemorrhages. Despite immediate high-dose antimycotic treatment, surgical debridement of necrotic tissue, and control of diabetes as a predisposing factor, the woman died 2 weeks after admission. Although fungal organisms are rarely detectable in CSF specimens from patients with mycotic infections of the central nervous system, comprehensive CSF examination is beneficial in the diagnosis of rhinocerebral mucormycosis. Furthermore, a concerted team approach, systemic antifungal agents and early surgical intervention seem to be crucial for preventing rapid disease progression.

Role of the serotonin transporter promoter polymorphism in anxiety-related traits.

BACKGROUND: The heritability of interindividual variation in anxiety and other aspects of personality establishes that variants of genes influence these traits. A functional polymorphism in the promoter of the human serotonin transporter gene (SLC6A4*C) was identified and found to be linked to an anxiety-related personality trait, Neuroticism. The polymorphism affects gene transcription and, ultimately, gene function. We have attempted to confirm the role of SLC6A4*C in anxiety-related personality traits by sibpair analysis and association studies. METHODS: Sibpair linkage analysis and association study were performed in 655 Finns. The index cases were 182 alcoholic criminal offenders, through which 258 relatives were ascertained to obtain 366 sibpairs. In addition, 215 unrelated population controls were collected. Each individual was psychiatrically interviewed, blind-rated for DSM-III-R diagnoses, and assessed with the Tridimensional Personality Questionnaire. RESULTS: The sibpair analysis revealed a positive linkage between SLC6A4*C and the 2 anxiety-related subdimensions of Harm Avoidance: HA1 (Anticipatory Worry) and HA2 (Fear of Uncertainty) (P = .003). However, there was no consistent association between SLC6A4*C and any Tridimensional Personality Questionnaire trait. CONCLUSIONS: In the present study we replicated the relationship of SLC6A4*C to anxiety by sibpair linkage analysis but found no evidence of association, raising the question of whether SLC6A4*C locus is itself affecting anxiety or is linked to another still unknown functional variant.

Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets.

The human serotonin transporter (5-HTT), encoded by a single gene on chromosome 17q11.2, is expressed in brain and blood cells. 5-HTT is implicated in mood and anxiety regulation, and is where antidepressant and antianxiety drugs initially act in the brain. A 5-HTT-linked promoter region (5-HTTLPR) insertion/deletion polymorphism with long (l) and short (s) forms affects transporter expression and function. The s variant reduced 5-HTT gene transcription in a reporter gene construct and human lymphoblasts, resulting in reduced transporter levels and 5-HT uptake, acting as a dominant allele. In this study, we investigated the expression and function of 5-HTT in platelets from healthy male volunteers. The l variant was associated with more rapid initial platelet 5-HT uptake (Vmax), the index of platelet 5-HTT function most clearly heritable, while the s allele was dominant. The 5-HTTLPR genotype had no effect on platelet [3H]paroxetine binding (Bmax), affinity for [3H]5-HT or [3H]paroxetine, or 5-HT content. The 5-HT uptake findings support a functional difference in the two 5-HTTLPR variants, reinforcing their attractiveness as candidate genes in neuropsychiatric research.

Serotonin transporter (5-HTT) gene and bipolar affective disorder.

Interactions with antidepressants, as well as other biochemical evidence, implicate the serotonin transporter 5-HTT in the etiology of affective disorders. However, genetic studies have produced conflicting results concerning an association of 5-HTT with bipolar disorder. We examined a variable number tandem repeat in the regulatory region of this gene to investigate the possible contribution of 5-HTT to bipolar disorder susceptibility in a 22-pedigree series. By affected-sib-pair analysis and the transmission/disequilibrium test, we found no significant linkage or association of 5-HTT to bipolar disorder. During the course of this study, we adapted a PCR technique designed to amplify long templates to replicating long GC stretches with complex structure. We also refined the location of 5-HTT by radiation hybrid mapping, placing the locus between D17S1294 and SHGC11022 on 17q11.2.

Gene structure and 5'-flanking regulatory region of the murine serotonin transporter.

By modulating the magnitude and duration of postsynaptic responses, carrier-facilitated serotonin (5-HT) transport into and release from the presynaptic neuron is central to the fine tuning of serotonergic neurotransmission. The 5-HT transporter (5-HTT) is the prime target for widely used antidepressants, psychostimulants, drugs of abuse and neurotoxins. We have isolated the gene encoding the murine 5-HTT and determined the sequence of all exons including adjacent intronic regions and approximately 3.6 kb of the 5'-flanking regulatory region. The murine 5-HTT gene is composed of 14 exons spanning approximately 34 kb. The single gene transcript after splicing is 2744 bp in length and it contains 186 bp of 5' untranslated region (5'-UTR) and 668 bp of 3'-UTR. A TATA-like motif and several potential binding sites for transcription factors including AP1, AP2, AP4, SP1 as well as CRE- and GRE-like motifs are present in the GC-rich 5'-flanking region. The characterization of murine 5-HTT cDNA and genomic organization will facilitate studies of 5-HT uptake function with molecular pharmacologic and transgenic strategies as well as investigations of its role in quantitative traits and psychiatric disorders.

Direct sequencing of the reserpine-sensitive vesicular monamine transporter complementary DNA in unipolar depression and manic depressive illness.

The reserpine model and the reduced monoamine hypothesis of the depressive symptom spectrum suggest that the reserpine-sensitive brain vesicular monoamine transporter (VMT) is a candidate for susceptibility to affective disorder. VMT nonselectively accumulates cytoplasmic biogenic monoamine neurotransmitters into the storage vesicles of presynaptic neurons and blood platelets. Complementary DNA (cDNA) synthesized from platelet VMT mRNA was analyzed in 17 patients meeting DSM-III-R diagnostic criteria for major depressive or bipolar disorder and in four healthy controls, using polymerase chain reaction (PCR) amplification and direct sequencing. PCR sequencing of the protein coding region failed to reveal changes in the deduced amino acid sequence of the platelet/brain VMT (approximately 36,000 base pairs sequence screened). The results indicate that alterations in the primary structure of the VMT are not generally involved in the pathogenesis of unipolar depression and manic depressive illness.

The appetite suppressant d-fenfluramine induces apoptosis in human serotonergic cells.

Fenfluramine is an amphetamine analogue which has been widely used in the treatment of obesity. In rodents, non-human primates, and humans, fenfluramine is associated with some indices of neurotoxicity, as well as pulmonary hypertension and cardiac valve pathology. In the present study, d-fenfluramine was found to be cytotoxic to the serotonin (5-HT) transporter (5-HTT) expressing human placental choriocarcinoma cells. d-Fenfluramine caused DNA fragmentation and apoptosis. Apoptosis was not observed after the 5-HTT had been blocked by fluoxetine, indicating that intact 5-HTT function is required for d-fenfluramine to induce programmed cell death. These observations in a human cell line may reflect a possible mechanism associated with the risks of fenfluramine administration in several species, including humans.

Cellular localization and expression of the serotonin transporter in mouse brain.

The high-affinity serotonin (5-HT) transporter (5-HTT) plays an important role in the removal of extracellular serotonin, thereby modulating and terminating the action of this neurotransmitter at various pre- and post-synaptic serotonergic receptors and heteroreceptors. In order to characterize the anatomical distribution of the 5-HTT in mouse brain, in situ hybridization histochemistry using 35S-labeled riboprobes was performed. These results were compared with 5-HTT binding site distribution as evaluated by [125I]RTI-55 autoradiography. High levels of 5-HTT mRNA were detected in all brain stem raphe nuclei, with variations in labeling among the various subnuclei. Those brain areas known to possess serotonergic cell bodies stained intensely for both 5-HTT mRNA and 5-HTT binding sites. In contrast to previous findings in rat brain, the highest densities of 5-HTT sites were found in areas outside the raphe complex, particularly in the substantia nigra, globus pallidus, and superior colliculi.

Differential regulation of adenosine A(1) and A(2A) receptors in serotonin transporter and monoamine oxidase A-deficient mice.

The serotonin (5HT) transporter (5HTT) removes 5HT from the synaptic cleft and is thus critical to the control of serotonergic neurotransmission. Mice with a targeted inactivation of the 5HTT represent a novel and unique tool to study serotonergic system functioning. Because the release of 5HT is regulated by adenosine, we investigated 5HTT-deficient mice for possible adaptive changes of adenosine A(1) and A(2A) receptors. A(1) and A(2A) receptors were studied by means of quantitative autoradiography using the radioligands [3H]8-cyclopentyl-1,3-dipropylxanthine and [3H]CGS 21680, respectively. A comparison of 5HTT knockout versus control mice revealed upregulation of A(1) receptors in the dorsal raphe nucleus (DRN, +21%), but not in any of the serotonergic projection areas, and downregulation of A(2A) receptors in basal ganglia. The adaptive changes of A(1) and A(2A) receptors in 5HTT-deficient mice are likely to represent a compensatory neuroprotective effect mediated by the adenosinergic modulatory system. For comparison, these receptors were also studied in monoamine oxidase A (MAOA) knockout mice and in 5HTT/MAOA double knockout mice. 5HTT/MAOA double knockout mice showed adaptive changes of adenosine A(1) and A(2A) receptors similar to 5HTT knockout mice, while investigation of MAOA-deficient mice revealed an upregulation of A(2A) receptors, which may relate to a role of both MAOA and adenosine A(2A) receptors in anxiety.

Molecular heterogeneity of neurotransporters: implications for neurodegeneration.

Neurotransporters are high-affinity transport proteins located in the plasma membrane of both presynaptic nerve and glial cells that mediate the removal of neurotransmitters from the synaptic cleft or represent intracellular transport systems that concentrate neurotransmitters in synaptic vesicles. They comprise three subgroups, Na+/Cl(-)- or Na+/K(+)-dependent cell surface transporters and H(+)-dependent transporters associated with synaptic vesicles. The new insights into neurotransporter diversity provide the means for novel approaches of studying neurotransmitter uptake processes at the molecular level, such as substrate translocation and antagonist binding as well as regulation of gene expression, of intracellular trafficking, and of posttranslational modification. Moreover, modeling neurotransporter-related disorders and therapeutic strategies in genetically engineered animals are now feasible research strategies. Through an improved understanding of the modulation of neurotransporter function in the brain, it may be possible to identify the molecular factors underlying the etiopathogenesis and pathophysiology of neurodegenerative disorders. Due to their specificity for distinct neuronal systems, neurotransporters and their genes are potential targets for novel therapeutic strategies.

[Crossed central neuropathic pain syndrome after bacterial meningoencephalitis]. / Gekreuztes zentral-neuropathisches Schmerzsyndrom nach bakterieller Meningoenzephalitis.

We report on a 48 year old female patient who acquired a bacterial meningoencephalitis as a result of a cervical myelography. Examination of the cerebrospinal fluid (CSF) revealed 309 cells per microliter and Streptococcus acidominimus was isolated as the infectious agent. Cranial MRI demonstrated disseminated lesions predominantly in the pontine and medullary brain stem as well as in thalamic nuclei. The patient developed a crossed central neuropathic pain syndrome. Neurological examination showed mechanic allodynia and hyperpathy along the left-sided extremities as well as right-sided neuropathic facial pain. On the MRI a dorsolateral medullary lesion on the right side, in the territory of the posterior inferior cerebellar artery was found. The localization of the lesion is suggestive of involvement of the spinal trigeminal tract or nucleus and the spinothalamic tract that would explain the neuropathic pain syndrome.A combination of gabapentine and amitriptyline reduced the pain markedly whereas opioids failed to provide sufficient analgesia.

[Coincidence of Huntington chorea and epilepsy]. / Koinzidenz von Chorea Huntington und Epilepsie.

We report on a patient suffering from epilepsy and severe personality changes. Huntington disease was diagnosed by molecular-biological investigation. Clinical characteristics are discussed on the basis of modern concepts of the genetic mechanism. Neuroradiological investigation revealed marked cerebellar atrophy, while typical findings of Huntington disease, such as caudate nucleus volume loss, were lacking. The cerebellar atrophy could be attributable either to long-term phenytoin-medication or to the pathological process itself.

Cavum veli interpositi and psychotic disorder in a monocygotic twin.

The case of monocygotic twins discordant for a psychotic disorder is presented. An anomaly of the septum pellucidum, a so-called cavum veli interpositi was found in the psychotic twin while his brother showed no such anomaly. Previous studies have shown a higher prevalence of septum pellucidum anomalies in schizophrenic patients. Abnormalities of the septum pellucidum may be associated with disturbed neuronal development in distinct limbic brain areas which cannot yet be visualized yet by brain imaging techniques. The finding of the cavum veli interpositi in the psychotic twin could be incidental; however, it may indicate a dysgenic process in early brain development and, thus, play a significant role in the etiology of psychosis.

Allelic variation of human serotonin transporter gene expression.

Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic responses, carrier-facilitated 5-HT transport into and release from the presynaptic neuron are essential for the fine tuning of serotonergic neurotransmission. Interest in the mechanism of environmental factor-, disease-, and therapy-induced modification of 5-HT transporter (5-HTT) function and its impact on early brain development, event-related synaptic plasticity, and neurodegeneration is widespread and intensifying. We have recently characterized the human and murine 5-HTT genes and performed functional analyses of their 5'-flanking regulatory regions. A tandemly repeated sequence associated with the transcriptional apparatus of the human 5-HTT gene displays a complex secondary structure, represses promoter activity in nonserotonergic neuronal cells, and contains positive regulatory components. We now report a novel polymorphism of this repetitive element and provide evidence for allele-dependent differential 5-HTT promoter activity. Allelic variation in 5-HTT-related functions may play a role in the expression and modulation of complex traits and behavior.

Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene.

We have isolated and characterized the 5'-flanking region and the proximal polyadenylation site of the human 5-HT transporter gene. The major gene transcript is 2,793 bp in length and it contains 208 bp of 5'-untranslated region (5'-UTR) and 694 bases of 3'-UTR. While only a single mRNA species occurs in rats and mice, the most proximal signal for polyadenylation in the human gene appears to be highly degenerate in comparison to the rat and murine motif. This polyadenylation signal-like motif may lead to alternate usage of additional polyadenylation sites resulting in multiple mRNA species in humans. A TATA-like motif and several potential binding sites for transcription factors including AP1, AP2, SP1, and a cAMP response element (CRE)-like motif are present in the 5'-flanking region. A approximately 1.7 kb fragment beginning 217 bp downstream from the transcription start site, which had been ligated into a luciferase reporter vector and transiently expressed in JAR human placental choriocarcinoma cells, displayed both constitutive and forskolin/cholera toxin-induced promoter activity. Functional promoter mapping revealed that there are negative attenuating elements between bp -1,428 and -1,185 and positive elements between bp -1,184 and -78 from the transcription initiation site. Studies with deletional mutants also indicated that core promoter sequences are contained within 78 bp of the transcription start site and that regulation of cAMP-inducible promoter activity depends on multiple cis-acting elements including two AP1 binding sites and a single CRE-like element located at bp -99. Our findings suggest that (1) the 5-HT transporter gene promoter is active in human JAR cells, but inactive in 5-HT transporter-deficient human SK-N-SH neuroblastoma and HeLa cells, (2) the information contained within 1.4 kb of 5'-flanking sequence is sufficient to confer its cell-specific expression, (3) the promoter responds to cAMP induction, and (4) the expression of the 5-HT transporter gene is regulated by a combination of positive and negative cis-acting elements operating through a basal promoter unit defined by a TATA-like motif.