NG2 cells, a new trail for Alzheimer's disease mechanisms?

BACKGROUND: Neuron Glial 2 (NG2) cells are glial cells known to serve as oligodendrocyte progenitors as well as modulators of the neuronal network. Altered NG2 cell morphology and up-regulation as well as increased shedding of the proteoglycan NG2 expressed on the cell surface have been described in rodent models of brain injury. Here we describe alterations in the human NG2 cell population in response to pathological changes characteristic of Alzheimer's disease (AD). RESULTS: Immunohistological stainings of postmortem brain specimens from clinically diagnosed and postmortem verified AD patients and non-demented controls revealed reduced NG2 immunoreactivity as well as large numbers of NG2 positive astrocytes in individuals with high amyloid beta plaque load. Since fibrillar amyloid beta (Aß)1-42 is the major component of AD-related senile plaques, we exposed human NG2 cells to oligomer- and fibril enriched preparations of Aß1-42. We found that both oligomeric and fibrillar Aß1-42 induced changes in NG2 cell morphology. Further, in vitro exposure to fibrillar Aß1-42 decreased the NG2 concentrations in both cell lysates and supernatants. Interestingly, we also found significantly decreased levels of soluble NG2 in the cerebrospinal fluid (CSF) from clinically diagnosed AD patients compared to non-demented individuals. Additionally, the CSF NG2 levels were found to significantly correlate with the core AD biomarkers Aß1-42, T-tau and P-tau. CONCLUSION: Our results demonstrate major alterations in the NG2 cell population in relation to AD pathology which highlights the NG2 cell population as a new attractive research target in the search for cellular mechanisms associated with AD pathogenesis.

The birth and early evolution of the frontotemporal dementia (FTD) concept.

An historical overview of the development of the concept of frontotemporal dementia is presented, regarding the last 30 years, using as a backbone the conferences held on this theme, with a start in 1986 in Lund, Sweden. Since then, a dramatic increase in research activities and publications has rapidly expanded our knowledge in this field, a step necessary for the ultimate goal to find an effective treatment of this devastating disorder.

The accuracy of short clinical rating scales in neuropathologically diagnosed dementia.

OBJECTIVE: The overall aim was to evaluate to what extent the diagnosis of dementia subtypes, obtained by three clinical rating scales, concurred with postmortem neuropathologic (NP) diagnosis of Alzheimer disease (AD), frontotemporal dementia (FTD), vascular dementia (VaD) and mixed AD/VaD. DESIGN: A prospective longitudinal clinical work-up with postmortem NP examination. PARTICIPANTS: Two hundred nine patients with dementia referred for clinical evaluation and follow-up. METHODS: The diagnostic scores in a set of three short clinical rating scales for AD, FTD, and VaD were evaluated against NP diagnoses. RESULTS: The sensitivity and specificity of the AD scale were 0.80 and 0.87, respectively, of the FTD scale 0.93 and 0.92, respectively, and of the Hachinski Ischemic Score (HIS, VaD diagnosis) 0.69 and 0.92, respectively. Cases with mixed AD/VaD generally presented a combination of high AD and ischemic scores. A preferred cutoff score of six was identified for both the AD and FTD scales. CONCLUSIONS: All three clinical rating scales showed a high sensitivity and specificity, in close agreement with final NP diagnosis-for the HIS a moderate sensitivity. These scales may thus be considered good diagnostic tools and are recommended for clinical and research center settings.

A factor analytic approach to symptom patterns in dementia.

Previous publications have shown a high diagnostic sensitivity and specificity of three short clinical rating scales for Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VaD) validated against neuropathological (NP) diagnoses. In this study, the aim was to perform an exploratory factor analysis of the items in these clinical rating scales. The study included 190 patients with postmortem diagnoses of AD (n = 74), VaD (n = 33), mixed AD/VaD (n = 31), or FTD (n = 52). The factor analysis produced three strong factors. Factor 1 contained items describing cerebrovascular disease, similar to the Hachinski Ischemic Score. Factor 2 enclosed major clinical characteristics of FTD, and factor 3 showed a striking similarity to the AD scale. A fourth symptom cluster was described by perception and expression of emotions. The factor analyses strongly support the construct validity of the diagnostic rating scales.

Early changes in 2-deoxy-2-[18F]fluoro-D-glucose metabolism in squamous-cell carcinoma during chemotherapy in vivo and in vitro.

AIM: The aim of this study was to investigate early changes in uptake of 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) in vivo and in vitro in a squamous-cell carcinoma (SCC) cell line originating from a human head and neck SCC during cytotoxic therapy with respect to metabolism in tumor cells and in surrounding stromal tissue. MATERIALS AND METHODS: In 60 nude mice with xenografted SCC, 50 animals were treated with cisplatin. Early changes in the tumor FDG uptake following therapy were evaluated sequentially with phosphor imaging. Using this technique, areas with focal hypermetabolism were detected. The cells creating the focal hypermetabolism were then identified histopathologically on the corresponding sections. In addition, early FDG uptake versus the number of viable tumor cells was measured in vitro following cisplatin treatment. RESULTS: An early transient increase in FDG uptake in tumor cells was seen on day 1 in treated tumors, followed by a rapid decrease confirmed by subsequent tumor regression. This metabolic flare was present in all treated tumors but not in the controls. In vitro, an increase in FDG uptake per cell was observed. CONCLUSIONS: Our results provide new insights into the early metabolic changes in squamous-cell carcinomas subjected to cytotoxic therapy and thus contribute to the discussion on the feasibility of early predictive PET studies.

Increased blood-brain barrier permeability in mammalian brain 7 days after exposure to the radiation from a GSM-900 mobile phone.

Microwaves were for the first time produced by humans in 1886 when radio waves were broadcasted and received. Until then microwaves had only existed as a part of the cosmic background radiation since the birth of universe. By the following utilization of microwaves in telegraph communication, radars, television and above all, in the modern mobile phone technology, mankind is today exposed to microwaves at a level up to 10(20) times the original background radiation since the birth of universe. Our group has earlier shown that the electromagnetic radiation emitted by mobile phones alters the permeability of the blood-brain barrier (BBB), resulting in albumin extravasation immediately and 14 days after 2h of exposure. In the background section of this report, we present a thorough review of the literature on the demonstrated effects (or lack of effects) of microwave exposure upon the BBB. Furthermore, we have continued our own studies by investigating the effects of GSM mobile phone radiation upon the blood-brain barrier permeability of rats 7 days after one occasion of 2h of exposure. Forty-eight rats were exposed in TEM-cells for 2h at non-thermal specific absorption rates (SARs) of 0mW/kg, 0.12mW/kg, 1.2mW/kg, 12mW/kg and 120mW/kg. Albumin extravasation over the BBB, neuronal albumin uptake and neuronal damage were assessed. Albumin extravasation was enhanced in the mobile phone exposed rats as compared to sham controls after this 7-day recovery period (Fisher's exact probability test, p=0.04 and Kruskal-Wallis, p=0.012), at the SAR-value of 12mW/kg (Mann-Whitney, p=0.007) and with a trend of increased albumin extravasation also at the SAR-values of 0.12mW/kg and 120mW/kg. There was a low, but significant correlation between the exposure level (SAR-value) and occurrence of focal albumin extravasation (r(s)=0.33; p=0.04). The present findings are in agreement with our earlier studies where we have seen increased BBB permeability immediately and 14 days after exposure. We here discuss the present findings as well as the previous results of altered BBB permeability from our and other laboratories.

Blood-brain barrier permeability and nerve cell damage in rat brain 14 and 28 days after exposure to microwaves from GSM mobile phones.

We investigated the effects of global system for mobile communication (GSM) microwave exposure on the permeability of the blood-brain barrier and signs of neuronal damage in rats using a real GSM programmable mobile phone in the 900 MHz band. Ninety-six non-anaesthetized rats were either exposed to microwaves or sham exposed in TEM-cells for 2 h at specific absorption rates of average whole-body Specific Absorption Rates (SAR) of 0.12, 1.2, 12, or 120 mW/kg. The rats were sacrificed after a recovery time of either 14 or 28 d, following exposure and the extravazation of albumin, its uptake into neurons, and occurrence of damaged neurons was assessed. Albumin extravazation and also its uptake into neurons was seen to be enhanced after 14 d (Kruskal Wallis test: p = 0.02 and 0.002, respectively), but not after a 28 d recovery period. The occurrence of dark neurons in the rat brains, on the other hand, was enhanced later, after 28 d (p = 0.02). Furthermore, in the 28-d brain samples, neuronal albumin uptake was significantly correlated to occurrence of damaged neurons (Spearman r = 0.41; p < 0.01).

Histopathological examinations of rat brains after long-term exposure to GSM-900 mobile phone radiation.

In order to mimic the real life situation, with often life-long exposure to the electromagnetic fields emitted by mobile phones, we have investigated in a rat model the effects of repeated exposures under a long period to Global System for Mobile Communication-900 MHz (GSM-900) radiation. Out of a total of 56 rats, 32 were exposed once weekly in a 2-h period, for totally 55 weeks, at different average whole-body specific absorption rates (SAR) (of in average 0.6 and 60 mW/kg at the initiation of the experimental period). The animals were exposed in a transverse electromagnetic transmission line chamber (TEM-cell) to radiation emitted by a GSM-900 test phone. Sixteen animals were sham exposed and eight animals were cage controls, which never left the animal house. After behavioural tests, 5-7 weeks after the last exposure, the brains were evaluated for histopathological alterations such as albumin extravasation, dark neurons, lipofuscin aggregation and signs of cytoskeletal and neuritic neuronal changes of the type seen in human ageing. In this study, no significant alteration of any these histopathological parameters was found, when comparing the GSM exposed animals to the sham exposed controls.

Radiofrequency and extremely low-frequency electromagnetic field effects on the blood-brain barrier.

During the last century, mankind has introduced electricity and during the very last decades, the microwaves of the modern communication society have spread a totally new entity--the radiofrequency fields--around the world. How does this affect biology on Earth? The mammalian brain is protected by the blood-brain barrier, which prevents harmful substances from reaching the brain tissue. There is evidence that exposure to electromagnetic fields at non thermal levels disrupts this barrier. In this review, the scientific findings in this field are presented. The result is a complex picture, where some studies show effects on the blood-brain barrier, whereas others do not. Possible mechanisms for the interactions between electromagnetic fields and the living organisms are discussed. Demonstrated effects on the blood-brain barrier, as well as a series of other effects upon biology, have caused societal anxiety. Continued research is needed to come to an understanding of how these possible effects can be neutralized, or at least reduced. Furthermore, it should be kept in mind that proven effects on biology also should have positive potentials, e.g., for medical use.

Cognitive impairment in rats after long-term exposure to GSM-900 mobile phone radiation.

Considering the frequent use of mobile phones, we have directed attention to possible implications on cognitive functions. In this study we investigated in a rat model the long-term effects of protracted exposure to Global System for Mobile Communication-900 MHz (GSM-900) radiation. Out of a total of 56 rats, 32 were exposed for 2 h each week for 55 weeks to radio-frequency electromagnetic radiation at different SAR levels (0.6 and 60 mW/kg at the initiation of the experimental period) emitted by a (GSM-900) test phone. Sixteen animals were sham exposed and eight animals were cage controls, which never left the animal house. After this protracted exposure, GSM-900 exposed rats were compared to sham exposed controls. Effects on exploratory behaviour were evaluated in the open-field test, in which no difference was seen. Effects on cognitive functions were evaluated in the episodic-like memory test. In our study, GSM exposed rats had impaired memory for objects and their temporal order of presentation, compared to sham exposed controls (P = 0.02). Detecting the place in which an object was presented was not affected by GSM exposure. Our results suggest significantly reduced memory functions in rats after GSM microwave exposure (P = 0.02).

Identification and characterization of frontal lobe degeneration: historical perspective on the development of FTD.

This is a historical account of the development of the concept frontotemporal dementia, beginning with our discovery in the late 60s of a simple degenerative form. It was named frontal lobe degeneration of non-Alzheimer type to clearly separate it from the then almost totally dominating diagnosis Alzheimer disease. In the absence of immunohistochemical methods for specific disease markers, we had to rely solely on structural features. Later, from the 80s, the successively introduced methods to show glial acidic protein, tau, synaptophysin, ubiquitin, and other markers confirmed our impression of a simple type of degeneration. These methods also added further forms with additional features, and from the 90s genetics has contributed new disease characteristics, all these advances leading up to the present conceptual structure of frontotemporal lobar degeneration.

Clinical manifestations in neuropathologically defined subgroups of vascular dementia.

AIMS: To study cardio-cerebrovascular disease and clinical features, such as falls, dizziness/unsteadiness, urinary incontinence, hallucinations/delusions and delirium in neuropathologically defined subgroups of vascular Dementia (VaD): pure Small Vessel Dementia (SVD), combined SVD and Alzheimer's disease (SVD-AD), pure Large Vessel Dementia (LVD) and pure Hypoxic Hypoperfusive Dementia (HHD), and to analyse the clinical differences between these groups. MATERIALS AND METHODS: From 175 consecutive cases with neuropathologically verified VaD cases with pure SVD (n = 36) and SVD-AD (n = 38) with varying severity of AD pathology were selected and studied with respect to cardio-cerebrovascular and other clinical features. Furthermore, a comparison between pure SVD, pure LVD (n = 7) and pure HHD (n = 6) was made. RESULTS: Neither cardiovascular symptoms, hypertension, Transitoric Ischemic Attacks (TIA) nor complete cerebrovascular lesions (CVL) differed significantly between the pure SVD and SVD-AD groups. However, a wide variation of clinical features were reported. The prevalence of cardiovascular features varied markedly in the pure groups, with the highest prevalence consistently found in the LVD group. Hypertension was common in the pure LVD and SVD-groups, while it was a rare finding in the HHD-group. TIA and/or CVL were, as expected, most common in the LVD-group. CONCLUSION: In conclusion, this longitudinal and retrospective study of VaD shows important clinical similarities as well as differences between pathologically defined subgroups. Hopefully these findings will contribute to a better understanding of etiopathogenetic and diagnostic issues and form a solid basis for possible treatment strategies in VaD.

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.

A clinico-pathological study of heart and brain lesions in vascular dementia.

All vascular dementia (VaD) cases, neuropathologically verified in a longitudinal prospective dementia project, were classified according to the vascular brain lesion type and related to the dementia type and cardiovascular pathology. From 1976 to 1995, there were 175 VaD cases, 49 of which were pure, without Alzheimer pathology and only one type of cerebrovascular lesion. Furthermore, it was found that 6 cases suffered hypoxic hypoperfusive disease, while 7 were found to have large vessel disease and 36 small vessel disease. In addition to Alzheimer pathology, more than one type of vascular brain pathology was found in the remaining 126 cases. In these cases, diagnosed in accordance with the predominant type of VaD, hypoxic-hypoperfusive lesions were found in 55, large vessel lesions in 50 and small vessel lesions in 110 cases. It should be stressed that 87% of all cases with hypoxic hypoperfusive lesions also had Alzheimer pathology. Cardiovascular and aortic pathologies were more prevalent in small vessel dementia than in the other VaD groups. Clinically diagnosed arterial hypertension was significantly associated with small vessel dementia, but not with hypoxic-hypoperfusive dementia. Cardiovascular symptoms varied considerably in frequency between different dementia groups. VaD is a heterogeneous group regarding lesions caused by different pathophysiological mechanisms and with different combinations of brain pathologies. It is therefore necessary to identify the various types of vascular brain lesions for a correlation with clinical symptoms and for diagnostic purposes in the search for risk factors and therapeutic strategies.

Frontotemporal dementia linked to chromosome 3.

A large pedigree with autosomal dominant frontotemporal dementia has been identified. Positional cloning has linked the disease gene to the pericentromeric region of chromosome 3. Clinical, neuropsychological, imaging, pathological and molecular genetic data are presented. The genetic mutation responsible for the disease has not been identified.

Regional cerebral blood flow and EEG in clinically diagnosed dementia with Lewy bodies and Alzheimer's disease.

This study was undertaken in order to compare regional cerebral blood flow (rCBF) and EEG findings of patients with clinically diagnosed dementia with Lewy bodies (clinDLB) and Alzheimer's disease (clinAD). Furthermore, within the clinDLB group to compare cases with and without neuropathologically verified Lewy bodies (LBs). When we studied 200 dementia cases in a prospective longitudinal dementia study, 48 had clinDLB and 45 clinAD in retrospective analyses. EEG information was analysed in 34 clinDLB and 28 clinAD patients and cerebral blood flow, measured with the Xe 133 inhalation method, in 26 clinDLB and 25 clinAD. There were no differences in EEG between the clinDLB and clinAD groups or between the cases with and without LBs. The rCBF patterns in the clinDLB and clinAD groups showed similar reductions in the temporoparietal areas. The rCBF in cases with LBs showed heterogeneous pathology. The imaging results in clinDLB and clinAD were strikingly similar. The EEG and rCBF could not differentiate between cases with or without LB. The study illustrates the lack of specific changes of EEG and rCBF in cases with LB pathology.