Arne Brun

Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia.

We have previously reported a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). Here we identify a mutation in CHMP2B, encoding a component of the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of this family. We also describe an additional missense mutation in an unrelated individual with FTD. Aberration in the endosomal ESCRTIII complex may result in FTD and neurodegenerative disease.

Regional pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading

The various structural components of the cortical degeneration of Alzheimers disease were defined and graded. The severity of the degenerative process was thus mapped in different cortical areas where neuronal numbers and cortical width were also measured and compared with controls. Contrary to the general opinion that the degenerative process is rather uniformly diffuse, though accentuated in the medial temporal and frontal cortex, we found a consistent and more elaborate pattern with clearcut regional differences. Thus the degeneration involved, besides basal medial temporal limbic areas, the posterior cingulate gyrus and superior parietal lobule particularly, with somewhat less marked changes in the inferior parietal lobule and inferior temporal gyri. The sensorimotor, calcarine and anterior cingulate areas of the cortex were notably spared until very late stages. This regionally variable severity of the degeneration was also parallelled by a regionally varying reduction in neuronal numbers and cortical width, and agrees with our previously published results of a regional pattern which closely correlates with clinical parameters, including symptom pattern and regional cerebral blood flow alterations.

Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: A prospective multicenter trial of the scandinavian glioblastoma study group

In a controlled, prospective, randomized investigation, started in 1974, 118 patients with supratentorial astrocytoma Grade III–IV were divided into three groups. Groups 1 and 2 received 45 Gy postoperatively to the whole supratentorial brain. Bleomycin in 15‐mg doses and a total dose of 180 mg or placebo was given intravenously three times a week, one hour prior to radiotherapy, during weeks 1,2,4 and 5. Group 3 received conventional care but no radiotherapy or chemotherapy. Median survival rates of patients were 10.8 months in Groups 1 and 2, and 5.2 months in Group 3, a statistically significant difference. With regard to performance, the patients in Group 3 deteriorated faster than patients in Groups 1 and 2. Bleomycin had no positive or negative influence on survival.

HISTOCHEMICAL INDICATIONS FOR LYSOSOMAL LOCALIZATION OF HEAVY METALS IN NORMAL RAT BRAIN AND LIVER

With a modified sulfide-silver method for the demonstration of heavy metals, hepatic parenchymal cells, Kupffer cells, neurons and glial cells were found normally to contain stainable cytoplasmic granules with a shape, size and distribution identical with that of lysosomes in the various cells studied. Previous studies have shown the lysosomes of mast cells and eosinophilic leukocytes normally to contain zinc. Iron has also been demonstrated in residual bodies in different tissues. Under pathologic conditions, such as Wilsons disease and experimentally induced intoxications, lysosomes have been shown to take up copper, mercury and lead. Our results suggest that heavy metals are normal constituents of lysosomes in a more general way than hitherto assumed.

A randomized study of chemotherapy with procarbazine, vincristine, and lomustine with and without radiation therapy for astrocytoma grades 3 and/or 4

The authors undertook a controlled, prospective, randomized study of 171 patients with supratentorial astrocytoma Grades 3 and/or 4 (classified according to Kernohan). All patients were given chemotherapy consisting of procarbazine, vincristine, and lomustine (CCNU) (PVC). Half of the patients received whole‐brain irradiation (RT) to a dose of 5800 cGy in the tumor‐bearing hemisphere and 5000 cGy in the contralateral hemisphere. After diagnosis of progressive tumor growth, patients received individual treatment. The endpoint of the study was time to progression, but cases were followed until the patients died. Median time to progression (MTP) for the whole randomized population was 21 weeks. Median survival time (MST) was 53 weeks; 18% of patients survived for 2 years or longer. Survival analysis showed that patients less than 50 years of age treated with PVC plus RT had significantly longer MTP (81 weeks) and MST (124 weeks) than all other patients. For patients less than 50 years of age treated with PVC alone, MTP was 21 weeks and MST was 66 weeks. For patients more than 50 years of age treated with PVC plus RT, MTP was 23 weeks and MST was 51 weeks; in the PVC group, MTP was 17 weeks and MST was 39 weeks. Age, Karnofsky index, areas of Grade 2, and absence of extensive necrosis in the tumor were significant prognostic factors in the univariate analyses. Patients less than 50 years of age treated with PVC plus RT had significantly longer survival (P = 0.037) when correcting for these factors in a multi‐variate analysis.

Blood-brain barrier permeability in rats exposed to electromagnetic fields used in wireless communication

Biological effects of radio frequency electromagnetic fields (EMF) on the blood‐brain barrier (BBB) have been studied in Fischer 344 rats of both sexes. The rats were not anaesthetised during the exposure. All animals were sacrificed by perfusion–fixation of the brains under chloralhydrate anaesthesia after the exposure. The brains were perfused with saline for 3–4 minutes, and thereafter perfusion fixed with 4% formaldehyde for 5–6 minutes. Whole coronal sections of the brains were dehydrated and embedded in paraffin and sectioned at 5 µm. Albumin and fibrinogen were demonstrated immunohistochemically and classified as normal versus pathological leakage. In the present investigation we exposed male and female Fischer 344 rats in a Transverse Electromagnetic Transmission line chamber to microwaves of 915 MHz as continuous wave (CW) and pulse‐modulated with different pulse power and at various time intervals. The CW‐pulse power varied from 0.001 W to 10 W and the exposure time from 2 min to 960 min. In each experiment we exposed 4–6 rats with 2–4 controls randomly placed in excited and non‐excited TEM‐cells respectively. We have in total investigated 630 exposed rats at various modulation frequencies and 372 controls. The frequency of pathological rats is significantly increased (p < 0.0001) from 62/372 (ratio: 0.17 ± 0.02) for control rats to 244/630 (ratio: 0.39 ± 0.03) in all exposed rats. Grouping the exposed animals according to the level of specific absorbed energy (J/kg) give significant difference in all levels above 1.5 J/kg. The exposure was 915 MHz microwaves either pulse modulated (PW) at 217 Hz with 0.57 ms pulse width, at 50 Hz with 6.6 ms pulse width or continuous wave (CW). The frequency of pathological rats (0.17) among controls in the various groups is not significantly different. The frequency of pathological rats was 170/481 (0.35 ± 0.03) among rats exposed to pulse modulated (PW) and 74/149 (0.50 ±0.07) among rats exposed to continuous wave exposure (CW). These results are both highly significantly different to their corresponding controls (p <0.0001) and the frequency of pathological rats after exposure to pulsed radiation (PW) is significantly less (p < 0.002) than after exposure to continuous radiation (CW).

Boron Neutron Capture Therapy for Glioblastoma Multiforme: Clinical Studies in Sweden.

A boron neutron capture therapy (BNCT) facility has been constructed at Studsvik, Sweden. It includes two filter/moderator configurations. One of the resulting neutron beams has been optimized for clinical irradiations with a filter/moderator system that allows easy variation of the neutron spectrum from the thermal to the epithermal energy range. The other beam has been designed to produce a large uniform field of thermal neutrons for radiobiological research. Scientific operations of the Studsvik BNCT project are overseen by the Scientific Advisory Board comprised of representatives of major universities in Sweden. Furthermore, special task groups for clinical and preclinical studies have been formed to facilitate collaboration with academia. The clinical Phase II trials for glioblastoma are sponsored by the Swedish National Neuro-Oncology Group and, presently, involve a protocol for BNCT treatment of glioblastoma patients who have not received any therapy other than surgery. In this protocol, p-boronophenylalanine (BPA), administered as a 6-h intravenous infusion, is used as the boron delivery agent. As of January 2002, 17 patients were treated. The 6-h infusion of 900 mg BPA/kg body weight was shown to be safe and resulted in the average blood–boron concentration of 24 μg/g (range: 15–32 μg/g) at the time of irradiation (approximately 2–3 h post-infusion). Peak and average weighted radiation doses to the brain were in the ranges of 8.0–15.5 Gy(W) and 3.3–6.1 Gy(W), respectively. So far, no severe BNCT-related acute toxicities have been observed. Due to the short follow-up time, it is too early to evaluate the efficacy of these studies.

Cortical synaptic changes and gliosis in normal aging, Alzheimer's disease and frontal lobe degeneration

The most important new development during recent years in the field of degenerative dementia concerns synaptic pathology. So far it has been investigated in some regions and some cortical laminae in Alzheimers disease (AD). The present communication is a more comprehensive study of all laminae in four different regions, the prefrontal, parietal, inferior temporal and posterior cingulate cortex. Against the background of normal aging, AD was compared with another degenerative disorder, frontal lobe degeneration of non-Alzheimer type (FLD). The synapse density was measured using synaptophysin as a marker. Astrocytes were also counted in the molecular layer. In normals, the cortex showed successively lower synaptic density from layer I to layer VI and relatively lowest density in the prefrontal cortex and a general decline with increasing age. A 46-49% decrease in synaptic density was found in all laminae in all regions of AD brains, a finding different from that in FLD. The number of astrocytes increased significantly in the prefrontal cortex both in AD and FLD but parietally only in AD. These results contribute to the understanding of normal synaptic organization of cortex, demonstrate the laminar and regional distribution of synaptic loss in AD and underscore the difference between AD and FLD. The gliosis appears to be secondary to the neurodegenerative changes. Synaptic loss is likely to be a common pathogenetic feature of neurodegenerative disorders and a likely cause of clinical symptoms and regional metabolic decrements in dementia.

Pathology and Pathophysiology of Cerebrovascular Dementia: Pure Subgroups of Obstructive and Hypoperfusive Etiology

The brains of 175 consecutive autopsy cases of dementia, clinically studied prospectively, were analyzed pathoanatomically with regard to type, size and site of lesions. Pure groups of vascular dementia caused by large or small vessel disease and by hypoperfusion could be defined. The infarcts were either complete with a more or less pronounced incomplete perifocal component or of an incomplete type only. Incomplete infarction appears to be an important and yet little appreciated cause of brain dysfunction. These groups could be used as a basis for a pathoanatomical classification of vascular dementias. Vascular dementia is much more common than generally assumed.

SURVIVAL AFTER SEVERE CEREBRAL ANOXIA WITH DESTRUCTION OF THE CEREBRAL CORTEX: THE APALLIC SYNDROME *

In the present paper eight deceased patients are described who had all been exposed to severe cerebral anoxia and survived for varying periods of time (one week to 17 years). All showed a uniform clinical symptomatology with complete loss of higher functions (speech, voluntary motor activity, emotional reactions, signs of memory), but with good retention of brain-stem functions, including spontaneous respiration. These patients could be aroused by afferent stimulation, responding by primitive motor reactions, chewing, swallowing, respiratory changes, etc. The EEG was in all cases highly depressed, and in some cases isoelectric. The supratentorial cerebral blood flow was very low in the most chronic cases, and less so in a case with shorter duration. Neuropathologic studies showed a uniform picture with severe anoxic changes and an almost total destruction and disappearance of the telencephalic neurons. The neuron loss was especially marked in the patients who survived for several years, in whom the cortex had been replaced by a thin gliotic and fibrous tissue. We have advocated the term “apallic syndrome” for states of the type described.’ This term implies a loss of the “pallium,” the cortical grey mantle that covers the telencephalon. It was introduced by Kretschmer* in 1940 to denote states with loss of telencephalic functions after severe anoxic, traumatic, infectious, degenerative, or cerebrovascular disorders. Gerstenbrand also included acute, and to some extent transient, states following trauma with failing respiration and systemic circulation, epileptic symptoms, tonic cerebral seizures, etc. His definition was therefore somewhat difficult to outline, and this might have been why the diagnosis “apallic syndrome” has been used very little in the English literature. Instead, a number of terms have been employed such as “prolonged unconsciousness,” “decorticate” or “decerebrate states,” or simply “severe stuporous dementia.” In the French literature terms like “coma prolongt” or sometimes “coma vigile” have been ad~oca ted .~ Some years ago Jennet and Plum suggested the term “persistent vegetative state” for similar types of patients6 Finally, Korein has introduced the term “cerebral death”