Patients with heart attacks are not valid models for medial temporal lobe amnesia. A neuropsychological and FDG-PET study with consequences for memory research

Equating the condition after cardiac arrest with that of medial temporal damage, and consequently medial temporal lobe amnesia, is questioned on the basis of results from a patient who was studied neuropsychologically as well as with static and dynamic imaging methods (MRI, PET) 6–9 months after a heart attack. The patient manifested severe and persistent anterograde and retrograde amnesia, as well as further cognitive deteriorations. While MRI only indicated non-specific cortical atrophy, PET revealed a severe bilateral affection of the thalamus and of both medial and lateral temporal cortices as well as occipito-parietal hypometabolism. The neuropsychological status indicates that patients with a diagnosis of cardiac arrest may suffer very severe and persistent cognitive deficits; the imaging analyses show that cardiac arrests may lead to quite severe and widespread brain damage which, however, may not be visible with current magnetic resonance imaging technology, but which is clearly apparent from positron emission tomography. These data suggest that patients with a condition after a heart attack may not be valid models for pure hippocampal—or even medial temporal lobe—pathology, as they may suffer much more widespread brain damage.     

Connexin 26 mutations in cases of sensorineural deafness in eastern Austria

Mutations in the connexin 26 (Cx26) gene (GJB2) are associated with autosomal nonsyndromic sensorineural hearing loss. This study describes mutations in the Cx26 gene in cases of familial and sporadic hearing loss (HL) by gene sequencing and identifies the allelic frequency of the most common mutation leading to HL (35delG) in the population of eastern Austria. For this purpose we have developed and applied a molecular beacon based real-time mutation detection assay. Mutation frequencies in the Cx26 gene of individuals from affected families (14 out of 46) and sporadic cases (11 out of 40) were 30.4% and 27.5%, respectively. In addition to known disease related alterations, a novel mutation 262 G-->T (A88S) was also identified. 35delG accounted for almost 77% of all Cx26 mutations detected and displayed an allelic frequency in the normal hearing population of 1.7% (2 out of 120). The high prevalence of the 35delG mutation in eastern Austria would therefore allow screening of individuals and family members with Cx26 dependent deafness by a highly specific and semi-automated method.     

Impairment of neocortical metabolism predicts progression in Alzheimer's disease

Progression rates of Alzheimer's disease (AD) vary considerably, and they are particularly difficult to predict in patients with mild cognitive impairment. We performed a prospective multicenter cohort study in 186 patients with possible or probable AD, mostly with presenile onset. In a cross-sectional analysis at entry, impairment of glucose metabolism in temporoparietal or frontal association areas measured with positron emission tomography was significantly associated with dementia severity, clinical classification as possible versus probable AD, presence of multiple cognitive deficits and history of progression. A prospective longitudinal analysis showed a significant association between initial metabolic impairment and subsequent clinical deterioration. In patients with mild cognitive deficits at entry, the risk of deterioration was up to 4.7 times higher if the metabolism was severely impaired than with mild or absent metabolic impairment. Copyrightz1999S.KargerAG, Basel     

Morphological changes in anaplastic gliomas treated with radiation and chemotherapy

Summary The effects of antineoplastic treatment on gliomas are related to tumour cell cycle and proliferation kinetics, glioma tissue architecture, and the surrounding environment. Morphological changes induced by radiation and chemotherapy are characterized by cell necrosis and severe alterations in cell and nuclear morphology caused by changes in the cell kinetic parameters which, however, may also occur spontaneously in untreated anaplastic gliomas.Comparative studies of cytological imprints and routine histological preparations of biopsy and autopsy specimens were performed in four groups of anaplastic astrocytomas and glioblastomas (78 cases) with postsurgical irradiation, combination chemotherapy, and CCNU treatment, and without specific postsurgical treatment (control group). Following radiation and chemotherapy, in addition to increased necrosis and vascular response, a variety of characteristic but nonspecific changes were observed in cell and nuclear morphology with prominent formation of multinucleated giant and monstrous cells, irregular and hyperchromatic nuclei, and severe cytoplasmic degeneration indicating both inhibition of cell division and cell damage. Statistically significant findings were a posttreatment increase in the number of multinucleated giant and monstrous cells and a decrease in the number of mitoses. These changes were more pronounced after chemotherapy than after radiation, while no significant dissimilarities were found between combination chemotherapy and CCNU. The implications of these changes on the mechanisms of antitumour treatment in anaplastic gliomas are discussed.

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Morphologische Veränderungen in anaplastischen Gliomen nach Strahlen- und Chemotherapie

Zusammenfassung Die Wirkung anuneoplastisdier Behandlung auf Gliome ist abhängig von der Tumorzeil- und Proliferationskinetik, der Gliomarchitektur und dem umgebenden Hirngewebe. Durch Strahlen- und Chemotherapie induzierte morphologische Veränderungen sind gekennzeichnet durch Zellnekrosen sowie schwere Zell- und Kernschäden durch Eingriffe in die Zellkinetik, doch können diese auch spontan in unbehandelten anaplastischen Gliomen auftreten.Vergleichsuntersuchungen von zytologischen Abstrichen und histologischen Routinepräparaten an Biopsie- und Autopsiematerial von 4 Gruppen anaplastischer Astrozytome und Glioblastome (78 Fälle) wurden nach postoperativer Strahlenbehandlung, Polychemotherapie und CCNU-Behandlung sowie ohne spezifische postoperative Therapie (Kontrollgruppe) vorgenommen. Nach Strahlen- und Chemotherapie fanden sich neben gesteigerter Nekrose und Gefäßreaktion verschiedene charakteristische, aber unspezifische Zell- und Kernveränderungen mit gesteigerter Neigung zur Bildung vielkerniger Riesen- und Monsterzellen, Kernhyperchromasie sowie schwerer Zytoplasmadegeneration als Hinweise auf Mitosestörungen und Zellschädigung. Nach antineoplastischer Therapie fand sich eine statistisch signifikante Zunahme von Riesen- und vielkernigen Monsterzellen sowie Abnahme der Mitosen, wobei diese Veränderungen nach Chemotherapie stärker ausgeprägt waren als nach Bestrahlung. Zwischen Polychemo- und CCNU-Behandlung ergaben sich keine wesentlichen Abweichungen. Die Bedeutung dieser zytologischen Spätbefunde auf die Effekte antineoplastischer Behandlung anaplastischer Gliome wird diskutiert.

     

Spastic paraplegia associated with addison's disease: Adult variant of adreno-leukodystrophy

Summary Clinical and pathological features of an adult variant of adreno-leukodystrophy (ALD) are presented. A male with clinical and laboratory signs of Addison's disease (AD) developed at age 22 a slowly progressing paraplegia with slight sensory deficits in both legs and bladder and sphincter dysfunctions; he died at age 24 in an AD crisis. Autopsy revealed hyperplasia of lymphatic tissues, lymphocytic infiltrates in various organs including the CNS and adrenocortical atrophy with prominence of large ballooned, sometimes bizarre and occasionally striated cortical cells. CNS lesions consisted in incomplete demyelination of long tracts of brain stem and spinal cord with accentuation in the pyramical tracts; in these areas, perivascular cuffs of epitheloid histiocytic cells contained a strongly PAS-positive non-sudanophilic material. Electron microscopy demonstrated massive storage of leaflet structures in perivascular histiocytes identical to the lamellar profiles previously described as specific for ALD. Some leaflets were found in close contact with compact lamellar arrays and with an electron-dense fingerprint material within astrocytes.In our case, the spastic paraplegia-AD syndrome which has been described previously in several clinical observations could be neuropathologically classified as an adult variant of ALD. Several differences to classical ALD occurring in young boys are stressed: the predominance of the endocrine disorder probably accounting for some of the perivascular lymphocytic infiltrates within the CNS; the absence of both clinical and pathological signs of diffuse cerebral involvement and the peculiar topistic pattern of CNS lesions and the very slow evolution of neurological signs paralleled by the absence of active sudanophilic demyelinating lesions. The possible mechanism of demyelination and the nature of the suggested metabolic defect in ALD are discussed. The ultrastructurally prominent leaflet structures may originate from myelin remnants, thus relating ALD to pathological storage of a myelin degradation product.

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Zusammenfassung Klinische und pathologische Befunde einer adulten Form der Adrenoleukodystrophie (ALD) werden dargestellt. Ein Patient mit klinischem Bild und Laboratoriumsbefunden der Addison-Krankheit (AD) entwickelte im Alter von 22 Jahren eine sehr langsam zunehmende Paraspastik mit geringer Hypaesthesie in beiden Beinen und Blasenund Mastdarmstörungen; er verstarb im Alter von 24 Jahren in einer AD-Krise. Bei der Autopsie fanden sich eine Hyperplasie des lymphatischen Apparats und lymphocytäre Infiltrate in verschiedenen Organen einschließlich des ZNS; beide Nebennieren waren atroph mit Hervortreten großer ballonierter, etwas bizarrer Rindenzellen mit gelegentlicher cytoplasmatischer Streifung. Im ZNS fanden sich pseudosystematische inkomplette Entmarkungen der langen Bahnen in Hirnstamm und Rückenmark mit Betonung der Pyramidenbahn, charakterisiert durch perivasale Manschetten epitheloider histiocytärer Zellen, die ein stark PAS-positives sudannegatives Material enthielten. Elektronenoptisch wurde eine massive Speicherung eines lamellären Materials in perivasalen Histiocyten nachgewiesen, welches mit den als spezifisch für die ALD angesehenen Einschlüssen übereinstimmte. Einige derartige Strukturen zeigten einen engen Zusammenhang mit kompakten Lamellenaggregaten und mit einem elektronendichten fingerprint-Material innerhalb von Astrocyten.In diesem Fall konnte das Paraplegie-AD-Syndrom, welches mehrfach bereits klinisch beschrieben worden war, aufgrund neuropathologischer Befunde als adulte Variante der ALD klassifiziert werden. Die Unterschiede dieser Form zur klassischen ALD, welche üblicherweise Knaben betrifft, werden hervorgehoben: das Überwiegen der endokrinen Symptomatik, was das Auftreten perivasaler Lymphocytensäume im ZNS zum Teil bedingen dürfte; das Fehlen klinischer und pathologischer Hinweise auf diffuse Beteiligung des Großhirns und die spezielle Topik der ZNS-Läsionen und die geringe Progredienz der neurologischen Symptomatik, welche im Einklang mit dem Fehlen florider sudanophiler Entmarkungsvorgänge steht. Der Mechanismus der Entmarkung und die Art der vermuteten metabolischen Störung bei der ALD werden diskutiert. Die elektronenoptisch charakteristischen lamellären Strukturen könnten aus dem Myelinabbau stammen, und damit könnte bei der ALD eine pathologische Speicherung eines Myelinabbauprodukts vorliegen.

     

Antipsychotic drugs and dopamine-mediated responses in Aplysia neurons

Summary The effect of antipsychotic drugs was tested on responses to micro-electrophoretically applied dopamine, acetylcholine and 5-hydroxy-tryptamine in identified neurons of the marine gastropod Aplysia californica. Fluphenazine was able to depress the response to DA in concentration of 10M, with 100M DA-responses of many neurons were blocked completely. Thioridazine (10 and 100M) and haloperidol (50M) were also effective in depressing DA-responses, while the non-antipsychotic phenothiazines mepazine (10 and 100M) and promethazine (100M) had only a slight action on DA-receptors. ACh-and 5-HT-responses were slightly affected only by high concentrations after long lasting perfusion. The investigated drugs had no persistent or only an insignificant effect on resting membrane potential and amplitude of action potentials of the neurons. With haloperidol depolarizing afterpotentials leading to double discharges were observed in some neurons. In a few instances spontaneous EPSPs disappeared with the DA-response under the influence of anti-psychotic drugs.The results render a direct neurophysiological evidence for the blockade of DA-receptors by antipsychotic drugs in correspondence to their clinical efficacy and agree with data from clinical observations and obtained in neurochemical, behavioral and indirect neurophysiological experiments.Supported by the österreichischen Fonds zur Förderung der wissenschaftlichen Forschung. —A preliminary report of a part of the results was published in Experientia30, 1318–1320 (1974).     

Delineation of brain tumor extent with [11C]L-methionine positron emission tomography: local comparison with stereotactic histopathology.

PURPOSE: Methyl-[11C]L-methionine ([11C]MET) positron emission tomography (PET) in brain tumors reflects amino acid transport and has been shown to be more sensitive than magnetic resonance imaging in stereotactic biopsy planning. It remains unclear whether the increased [11C]MET uptake is limited to solid tumor tissue or even detects infiltrating tumor parts. EXPERIMENTAL DESIGN: In 30 patients, a primary or recurrent brain tumor was suspected on magnetic resonance imaging. Patients were investigated with [11C]MET-PET before stereotactic biopsy. The biopsy trajectories were plotted into the [11C]MET-PET images with a newly designed C-based software program. The exact local [11C]MET uptake was determined within rectangular regions of interest of 4 mm in width and length aligned with the biopsy specimen. Individual histologic specimens were rated for the presence of solid tumor tissue, infiltration area, and nontumorous tissue changes. RESULTS: Receiver operating characteristics analysis demonstrated a sensitivity of 87% and specificity of 89% for the detection of tumor tissue at a threshold of 1.3-fold [11C]MET uptake relative to normal brain tissue. At this threshold, only 13 of 100 tumor positive specimen were false negative mainly in grade 2 astrocytoma. In grade 2 astrocytoma, mean [11C]MET uptake in the infiltration area was significantly higher than in solid tumor tissue (P < 0.003). CONCLUSIONS: [11C]MET-PET detects solid parts of brain tumors, as well as the infiltration area at high sensitivity and specificity. High [11C]MET uptake in infiltrating tumor of astrocytoma WHO grade 2 reflects high activity in this tumor compartment. Molecular imaging, with [11C]MET, will guide improved management of patients with brain tumors.     

Morphologic dysplasia in de novo acute myeloid leukemia (AML) is related to unfavorable cytogenetics but has no independent prognostic relevance under the conditions of intensive induction therapy: results of a multiparameter analysis from the German AML Cooperative Group studies.

PURPOSE: On the basis of cytomorphology according to the French-American-British (FAB) classification, we evaluated the prognostic impact of dysplastic features and other parameters in de novo acute myeloid leukemia (AML). We also assessed the clinical significance of the recently introduced World Health Organization (WHO) classification for AML, which proposed dysplasia as a new parameter for classification. PATIENTS AND METHODS: We analyzed prospectively 614 patients with de novo AML, all of whom were diagnosed by central morphologic analysis and treated within the German AML Cooperative Group (AMLCG)-92 or the AMLCG-acute promyalocytic leukemia study. RESULTS: Patients with AML M3, M3v, or M4eo demonstrated a better outcome compared with all other FAB subtypes (P <.001); no prognostic difference was observed among other FAB subtypes. The presence or absence of dysplasia failed to demonstrate prognostic relevance. Other prognostic markers, such as age, cytogenetics, presence of Auer rods, and lactate dehydrogenase (LDH) level at diagnosis, all showed significant impact on overall and event-free survival in univariate analyses (P <.001 for all parameters tested). However, in a multivariate analysis, only cytogenetics (unfavorable or favorable), age, and high LDH maintained their prognostic impact. Dysplasia was not found to be an independent prognostic parameter, but the detection of trilineage dysplasia correlated with unfavorable cytogenetics. CONCLUSION: Our results indicate that cytomorphology and classification according to FAB criteria are still necessary for the diagnosis of AML but have no relevance for prognosis in addition to cytogenetics. Our results suggest that the WHO classification should be further developed by using cytogenetics as the main determinant of biology. Dysplastic features, in particular, have no additional impact on predicting prognosis when cytogenetics are taken into account.