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Biomedical subjects

M Sjögren

Publications and source records attributed to M Sjögren.

At least 37 records · Page 2Linked to original sources
PubMed2001

Cerebrospinal fluid cytoskeleton proteins in patients with subcortical white-matter dementia.

The cerebrospinal fluid (CSF) levels of two cytoskeleton proteins, tau and the light subunit of neurofilament protein (NFL), both considered to reflect cerebral white-matter components, were investigated in a group of patients with a subtype of vascular dementia called 'subcortical white-matter dementia' (SWD). The group consisted of 25 demented patients with frontosubcortical brain syndromes, white-matter changes on computed tomography or magnetic resonance imaging and vascular disease or pronounced vascular risk factors. CSF-NFL was increased, whereas CSF-tau was normal, suggesting a differential involvement of the cytoskeleton in this patient group. The albumin ratio and the apolipoproteinE4 (ApoE4) allele status were also investigated. The albumin ratio was increased, indicating damage to the vessel walls with breakdown of the blood-brain barrier. No relationship was found between ApoE4 alleles and CSF levels of tau or NFL in this patient group. Besides presenting original data, the disease status of SWD is also discussed.

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PubMed2001

The exfoliation syndrome in cognitive impairment of cerebrovascular or Alzheimer's type.

The prevalence of exfoliation syndrome was studied in 39 patients suffering from dementia and cognitive impairment; a positive finding of exfoliation was detected in 11/39 of these patients. A comparison with an age-matched population survey showed that the prevalence of ocular exfoliation and the relative risk were significantly elevated. These results suggested that lesions related to the exfoliative process might be located also in the brain of patients suffering from dementia and cognitive impairment.

Adult↗
PubMed2001

Both total and phosphorylated tau are increased in Alzheimer's disease.

BACKGROUND: [corrected] Pathological tau protein concentrations in CSF are found in both Alzheimer's disease (AD) and frontotemporal dementia (FTD), but studies on brain tissue have suggested that the tau pathology in AD differs from that in FTD and that the difference may be related to the degree of phosphorylation. As CSF tau protein is increased after stroke, tau may also be implicated in the pathophysiology of vascular dementia, of which subcortical arteriosclerotic encephalopathy (SAE) is a putative subtype. OBJECTIVES: To investigate the nature of tau protein in CSF and the involvement of total CSF tau and phosphorylated CSF tau (phosphotau) in various types of dementia. METHODS: Using ELISAs for total tau and tau phosphorylated at Thr181 (phosphotau), the CSF concentrations of total tau and phosphotau were determined in patients with probable and possible AD (n=41 and 19, respectively), FTD (n=18), SAE (n=17), and Parkinson's disease (PD; n=15) and in age matched controls (n=17). All the antibodies stained the lower molecular weight bands, whereas only the antibodies that recognise phosphorylated tau stained the higher molecular bands. RESULTS: Both CSF tau and CSF phosphotau were increased in probable AD compared with FTD (p<0.001), SAE (p<0.001), PD (p<0.001), and controls (p<0.001). CSF phosphotau was increased in possible AD compared with FTD (p<0.001) and SAE (p<0.001). CSF tau and CSF phosphotau were positively correlated in all the groups. Molecular weight forms of tau ranging from 25 kDa to 80 kDa were found in the CSF CONCLUSION: Both phosphorylated and unphosphorylated tau isoforms were present in the CSF, and tau protein appeared in both truncated and full length forms. The results suggest that the CSF concentrations of tau and phosphotau are increased in about two thirds of patients with probable AD and in half of those with possible AD but are normal in FTD, SAE, and PD compared with normal aging. Values in the normal range do not exclude AD.

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PubMed2001

A new rating scale for age-related white matter changes applicable to MRI and CT.

BACKGROUND AND PURPOSE: MRI is more sensitive than CT for detection of age-related white matter changes (ARWMC). Most rating scales estimate the degree and distribution of ARWMC either on CT or on MRI, and they differ in many aspects. This makes it difficult to compare CT and MRI studies. To be able to study the evolution and possible effect of drug treatment on ARWMC in large patient samples, it is necessary to have a rating scale constructed for both MRI and CT. We have developed and evaluated a new scale and studied ARWMC in a large number of patients examined with both MRI and CT. METHODS: Seventy-seven patients with ARWMC on either CT or MRI were recruited and a complementary examination (MRI or CT) performed. The patients came from 4 centers in Europe, and the scans were rated by 4 raters on 1 occasion with the new ARWMC rating scale. The interrater reliability was evaluated by using kappa statistics. The degree and distribution of ARWMC in CT and MRI scans were compared in different brain areas. RESULTS: Interrater reliability was good for MRI (kappa=0.67) and moderate for CT (kappa=0.48). MRI was superior in detection of small ARWMC, whereas larger lesions were detected equally well with both CT and MRI. In the parieto-occipital and infratentorial areas, MRI detected significantly more ARWMC than did CT. In the frontal area and basal ganglia, no differences between modalities were found. When a fluid-attenuated inversion recovery sequence was used, MRI detected significantly more lesions than CT in frontal and parieto-occipital areas. No differences were found in basal ganglia and infratentorial areas. CONCLUSIONS: We present a new ARWMC scale applicable to both CT and MRI that has almost equal sensitivity, except for certain regions. The interrater reliability was slightly better for MRI, as was the detectability of small lesions.

Aging↗
PubMed2001

Tau and Abeta42 in cerebrospinal fluid from healthy adults 21-93 years of age: establishment of reference values.

BACKGROUND: Tau protein and the 42-amino acid form of beta-amyloid (Abeta42) measured in cerebrospinal fluid (CSF) have been proposed as potential biochemical diagnostic markers for Alzheimer disease. For the introduction of these assays in clinical practice, adequate reference values are of importance. METHODS: CSF samples were obtained from 231 neurologically and psychiatrically healthy individuals, 21-93 years of age, all with a MiniMental State examination score of 28 or above. Standardized ELISAs were used to measure tau and Abeta42 in CSF. Following IFCC recommendations, we used a rank-based method; the 0.90 and 0.10 fractiles were estimated to establish reference values for CSF-tau and CSF-Abeta42, respectively. Putative confounding factors, such as the influence of the passage of proteins from peripheral blood to CSF, influence of dysfunction of the blood-brain barrier, and freezing and thawing of CSF, were investigated. RESULTS: A correlation with age was found for CSF-tau (r = 0.60; P <0.001). Therefore, separate reference values for different age groups were established for CSF-tau: <300 ng/L in the group 21-50 years of age, <450 ng/L in the group 51-70 years of age, and <500 ng/L in the group 71-93 years of age. CSF-Abeta42 did not correlate with age (r = -0.045), and the reference value was set to >500 ng/L. No correlation was found between blood-brain barrier function and CSF-tau or CSF-Abeta42. CONCLUSIONS: These reference values can be applied when using CSF-tau and CSF-Abeta42 in clinical practice.

Adult↗
PubMed2000

Cytoskeleton proteins in CSF distinguish frontotemporal dementia from AD.

OBJECTIVE AND BACKGROUND: To investigate the CSF levels of tau and the light neurofilament protein (NFL) in patients with frontotemporal dementia (FTD) and other common dementia disorders as well as normal control subjects. Both proteins have been implicated in the pathophysiology of FTD. METHODS: CSF levels of tau and NFL were investigated in 18 patients with FTD, 21 patients with early-onset AD (EAD), 21 patients with late-onset AD (LAD), and 18 age-matched control subjects. RESULTS: Mean +/- SD CSF NFL levels were increased in patients with FTD (1442 +/- 1183 pg/mL; p < 0.05) and LAD (1006 +/- 727 pg/mL; p < 0.001) compared with control subjects (241 +/- 166 pg/mL) and in LAD compared with EAD (498 +/- 236 pg/mL; p < 0.05), and tended to be increased in FTD compared with EAD. CSF tau levels were increased in EAD (751 +/- 394 pg/mL; p < 0.01) and LAD (699 +/- 319 pg/mL; p < 0.01) compared with control subjects (375 +/- 170 pg/mL), and in EAD (p < 0.001) and LAD (p < 0. 01) compared with FTD (354 +/- 140 pg/mL). CSF NFL correlated positively with degree of cognitive impairment in FTD (r = 0.59; p < 0.05) and LAD (r = 0.61; p < 0.01). No significant differences were found in CSF NFL or CSF tau when comparing patients who did and did not possess the APOE-epsilon4 allele within each diagnostic group. CONCLUSION: The results suggest a differential involvement of these cytoskeleton proteins in FTD and EAD, with NFL primarily involved in the pathophysiology of FTD and tau in that of EAD. The increase in CSF NFL found in LAD might reflect the white-matter degeneration found in a proportion of LAD cases.

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PubMed2000

Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization.

Hyperphosphorylation of the microtubule-associated protein tau is specifically found in those brain cells affected in several tauopathies. Tau has also been consistently found to be present in the cerebrospinal fluid (CSF). Here we report the quantification in CSF of tau phosphorylated at Thr 181 using an immunoassay with a synthetic peptide for standardization. The choice of the peptide was based on fine mapping of a phospho-dependent antibody, AT270 (P(176)PAPKT(p)P(132))and a human specific tau antibody, HT7 (P(159)PGQK(163)). CSF-phospho-tau levels were increased in Alzheimer patients (23.5+/-10.1 pM, P<0.01) compared with age-matched controls (15.9+/-5.7 pM), while decreased in patients with frontotemporal dementia (8.6+/-3.9 pM; P<0.01). In every diagnostic group, a highly significant correlation was found between total tau and phospho-tau (Alzheimer's disease, r(2)=0.73; frontotemporal dementia, r(2)=0.43; Control, r(2)=0.42), suggesting that the degree of phosphorylation of CSF-tau changes in different clinical conditions.

Amino Acid Sequence↗
PubMed2000

CSF levels of tau, beta-amyloid(1-42) and GAP-43 in frontotemporal dementia, other types of dementia and normal aging.

Cerebrospinal fluid (CSF) levels of tau, beta-amyloid(1-42) and growth-associated protein 43 (GAP-43) were studied in patients with frontotemporal dementia (FTD; n = 17), Alzheimer's disease (AD; n = 60), subcortical white-matter dementia (SWD; n = 24), Parkinson's disease (PD; n = 23) and dysthymia (n = 19) and in age-matched controls (n = 32). CSF-tau was significantly increased only in AD, and CSF-beta-amyloid(1-42) was significantly decreased in AD and SWD as compared to controls, and in AD compared to FTD. CSF-GAP-43 was significantly decreased only in PD. The GAP-43/tau ratio was decreased in all the patient groups except the dysthymia group compared to controls. A positive correlation was found between CSF-GAP-43 and CSF-tau in all groups. The results suggest normal levels of CSF-tau and CSF-beta-amyloid(1-42) in FTD, which will aid in the clinical separation of FTD from AD. In SWD, decreased levels of CSF-beta-amyloid(1-42) suggest concomitant involvement of vascular and amyloid protein mechanisms.

Adult↗
PubMed2000

Lentivirus gene transfer in murine hematopoietic progenitor cells is compromised by a delay in proviral integration and results in transduction mosaicism and heterogeneous gene expression in progeny cells.

Human immunodeficiency virus type 1-based lentivirus vectors containing the green fluorescent protein (GFP) gene were used to transduce murine Lin(-) c-kit(+) Sca1(+) primitive hematopoietic progenitor cells. Following transduction, the cells were plated into hematopoietic progenitor cell assays in methylcellulose and the colonies were scored for GFP positivity. After incubation for 20 h, lentivirus vectors transduced 27.3% +/- 6.7% of the colonies derived from unstimulated target cells, but transduction was more efficient when the cells were supported with stem cell factor (SCF) alone (42. 0% +/- 5.5%) or SCF, interleukin-3 (IL-3), and IL-6 (53.3 +/- 1.8%) during transduction. The, vesicular stomatitis virus glycoprotein-pseudotyped MGIN oncoretrovirus control vector required IL-3, IL-6, and SCF for significant transduction (39.3 +/- 9.4%). Interestingly, only a portion of the progeny cells within the lentivirus-transduced methylcellulose colonies expressed GFP, in contrast to the homogeneous expression in oncoretrovirus-transduced colonies. Secondary plating of the primary GFP(+) lentivirus vector-transduced colonies revealed vector PCR(+) GFP(+) (42%), vector PCR(-) GFP(-) (46%), and vector PCR(+) GFP(-) (13%) secondary colonies, indicating true genetic mosaicism with respect to the viral genome in the progeny cells. The degree of vector mosaicism in individual colonies could be reduced by extending the culture time after transduction and before plating into the clonal progenitor cell assay, indicating a delay in the lentiviral integration process. Furthermore, supplementation with exogenous deoxynucleoside triphosphates during transduction decreased mosaicism within the colonies. Although cytokine stimulation during transduction correlates with higher transduction efficiency, rapid cell division after transduction may result in loss of the viral genome in the progeny cells. Therefore, optimal transduction may require activation without promoting intense cell proliferation prior to vector integration.

Animals↗
PubMed2000

Symptoms, vascular risk factors and blood-brain barrier function in relation to CT white-matter changes in dementia.

The aim was to study the frequently found white-matter changes on computerized tomography (CT) in patients with dementia and to relate these changes to clinical regional brain symptomatology, vascular factors, albumin ratio [indicator of blood-brain barrier (BBB) function] and other CT changes. The study included 85 patients, average age 71 +/- 8, with Alzheimer's disease (n = 56) and vascular dementia (n = 29), who underwent CT (Siemens Somatome DR 1) of the brain. They were inpatients in a psychiatric department specialized in dementia investigations. The degree of CT white-matter changes (absence, mild-moderate, severe) was the basis for the division of the patients into three groups. As the patients without white-matter changes were significantly younger than those with such changes, all statistical analyses were controlled for age. Subcortical symptomatology was significantly more frequent in the group with severe white-matter changes, whereas the reverse was true for parietal symptomatology. Diabetes mellitus, hypertension, ischemic cardiac disease and lacunas were significantly more common in patients with white-matter changes, whereas the frequency of transient ischemic attack/stroke episodes did not differ significantly between the groups. The albumin ratio was significantly higher in the groups with white-matter changes and highest in the group with severe white-matter changes. The findings indicate that white-matter changes in demented patients are at least partially an age- and stroke-independent disease manifestation of the vascular system and is associated with a specific symptom pattern. BBB dysfunction may be the link between the vasculature and the tissue damage.

Aged↗
PubMed1999

Neurofilament protein levels in CSF are increased in dementia.

The neurofilament is the major cytoskeletal structure of myelinated axons. In this study, CSF levels of the light subunit of the neurofilament protein (NFL) were increased in patients with vascular dementia (VAD), AD, and frontotemporal dementia (FTD) compared with neurologically healthy individuals. Because NFL is localized mainly in myelinated axons, these results suggest that the degeneration of white matter in these disorders causes the increased CSF NFL levels.

Aged↗
PubMed1998

Effect of airborne particles from selected indoor and outdoor environments on gap-junctional intercellular communication.

The effect of airborne particles from diesel exhaust, rubber and metal industry, urban air and biological sources (poultry, pig farming, compost industry) on gap-junctional intercellular communication (GJIC) were compared, using HEPA1c1c7 cells. Particles as such were compared with aqueous and organic extracts. Significant inhibition of GJIC by particle suspensions was only observed for the diesel and rubber samples, and for one biological sample (compost). Up to 83% of the inhibition of the whole suspension could be attributed to the particles as such. Washing the particles with organic solvents (aceton, methanol, hexane) did not result in a significant loss of activity from the particles, although the organic fractions showed a significant activity towards GJIC. More active organics was eluted from the rubber industry particles than from the diesel particles by the organic solvent. It is suggested that cancer promoting potential as measured by inhibition of GJIC may vary widely depending on the particle source, and that this effect may be exerted by the particles as such and/or by means of tightly bound bio-active material to the surface.

Agriculture↗
PubMed1997

The apolipoprotein E epsilon4 allele frequency is normal in fronto-temporal dementia, but correlates with age at onset of disease.

The apolipoprotein (apoE) epsilon4 allele was studied in fronto-temporal dementia (FTD), a diagnostic category including the specific disorders Pick's disease and frontal lobe degeneration of non-Alzheimer type (FLD). These dementing diseases have neuronal and synaptic degeneration in common with Alzheimer's disease (AD), for which the presence of the apoE epsilon4 allele is a known risk factor, and lowers the age of onset of disease. Previous studies on the apoE epsilon4 allele frequency in FTD have been inconclusive. The structural hallmarks of AD, allegedly linked to apoE presentation, neuritic plaques (NP), primarily composed of aggregates of beta-amyloid, and neurofibrillary tangles (NFT), primarily composed of hyperphosphorylated tau, are lacking in FTD. However, tau-positive cytoskeletal pathology is found in Pick's disease, but not in FLD. Resolving whether the epsilon4 frequency is increased in FTD or not may thus give clues to the pathogenetic mechanism of apoE in AD. We therefore studied apoE alleles in a well characterized material of FTD patients. The epsilon4 allele frequency was similar in 25 patients with FTD (14.0%) as compared with 26 healthy controls (13.5%). A post-mortem neuropathological examination was performed in 10 cases (nine had FLD and one Pick's disease). Our finding of a normal epsilon4 allele frequency in our group of FTD, principally consisting of FLD cases, support hypotheses involving differential binding of apoE to beta-amyloid and/or tau, in the development of beta-amyloid deposition and NP formation and/or tau hyperphosphorylation and NFT formation, for the pathogenetic role of apoE in AD. The age at onset was significantly lower (P < 0.01) in FTD patients possessing the epsilon4 allele (48.7 +/- 8.0 years) than in patients not possessing this allele (58.9 +/- 7.6 years). We conclude that, although the apoE epsilon4 allele frequency is not increase in FTD, the epsilon4 allele is not an etiological factor, but may rather be an accelerating factor in the degenerative process of FTD, thereby resulting in an earlier presentation of the disorder in individuals predisposed to develop FTD.

Adult↗
PubMed1997

Symptomatological characteristics distinguish between frontotemporal dementia and vascular dementia with a dominant frontal lobe syndrome.

OBJECTIVE: Our hypothesis was that patients with vascular dementia and a dominating frontal lobe syndrome have a symptomatology that reflects a more widespread lesion compared with patients with frontotemporal dementia. DESIGN: Patients with vascular dementia and a dominating frontal lobe syndrome (VAD-F; N = 11) were compared with regard to clinical symptoms and imaging features on CT scans of the brain with patients with frontotemporal dementia (FTD; N = 21). SETTING: A neuropsychiatric diagnostic ward. PATIENTS: Thirty-two inpatients, aged 48-78 years, with frontotemporal dementia or vascular dementia. MEASURES: Relatives were questioned about the initial symptoms. At the clinical investigation, mental and neurological symptoms and signs were recorded using the STEP method (stepwise comparative status analysis). CT scan features of the brain were evaluated by a trained neuroradiologist. The GBS-i (Gottfries-Bråne-Steen, intellectual variables) scale was used to measure the degree of dementia. RESULTS: At the onset of dementia, loss of memory (p < 0.001), sudden onset (p < 0.001), confusion (p < 0.05) and unspecified neurological signs (p < 0.05) had been significantly more frequent in the VAD-F group. At the time of the clinical investigation, lack of social awareness and presence of primitive reflexes were more frequent in the FTD group (p < 0.01 and p < 0.05, respectively) and visuospatial deficits more frequent in the VAD-F group (p < 0.05). CT of the brain showed that, apart from brain infarcts (present only in the VAD-F group), paraventricular leukoaraiosis was significantly more pronounced in the VAD-F group (p < 0.05). The groups did not differ with respect to age, age at onset or level of dementia. CONCLUSION: The findings support our hypothesis.

Age of Onset↗
PubMed1997

Induction of germline-length mutations at the minisatellites PC-1 and PC-2 in male mice exposed to polychlorinated biphenyls and diesel exhaust emissions.

PC-1 and PC-2 are hypervariable mouse minisatellites. The rates of spontaneous germline-length mutation have been shown to vary between different mouse strains. PC-1 is composed of GGCAG repeat units and PC-2 of GGCAGGA. Minisatellites frequently mutate by gaining or losing repeat units. Such length mutations in mini- and microsatellites have been associated with human disease and may therefore be an important endpoint in genetic toxicity testing. Carcinogenic activity of many chemicals is associated with their ability to induce heritable mutations. Since minisatellites are highly prone to mutate to new lengths, which can be assayed by Southern analysis, we used this method to detect heritable genetic effects in mice. Male mice exposed to diesel exhausts and/or polychlorinted biphenyls (PCB) were investigated for effects on the germline mutation frequenallele lengths in parents and offspring. For PC-1 significantly higher mutation frequencies were found in males treated with diesel exhausts + PCB (6 of 35 alleles) and with PCB alone (6 of 51 alleles) as compared to the males in the control group (0 of 43 alleles). The mutation frequency in the diesel exhaust group was not significantly increased (2 of 43 alleles). For PC-2 the only mutation found occurred in the PCB group (1 of 51 alleles). This in vivo study demonstrates--for the first time--chemically induced minisatellite mutations in the germline.

Animals↗
PubMed1996

Relevance of different biological assays in assessing initiating and promoting properties of polycyclic aromatic hydrocarbons with respect to carcinogenic potency.

The results from assays that describe biological effects of polycyclic aromatic hydrocarbons (PAH) were explored using multivariate methods. Based on the availability of data, 29 PAH were included in the study. Five variables described the carcinogenic potency in rodents of the PAH. Biological effects were assayed using 14 variables. These included bacterial mutagenicity, enhancement and inhibition of bacterial mutagenicity, Ah receptor (AhR) affinity, and induction of enzymes that bioactivate many PAH to proximal bacterial mutagens. A principal components analysis (PCA) showed that the highest correlations with the cancer data were observed for variables describing AhR affinity, whereas bacterial mutagenicity data were poorly correlated with cancer data. When a partial least squares (PLS) regression analysis was applied, only one bacterial mutagenicity variable, but all AhR affinity variables were statistically relevant to describe carcinogenic potency. The latter variables were also correlated with the inhibition of bacterial mutagenicity of benzo[a]pyrene. It was concluded that structural requirements for AhR affinity are the same as those required for metabolism by enzymes that bioactivate benzo(a)pyrene. Negative correlations between mutagenicity and induction of enzymes were observed. The roles of cancer initiation and cancer promotion are discussed regarding the biological properties studied. It is proposed that bacterial mutagenicity reflects the cancer initiation potency, whereas the AhR affinity reflects the promotive effect of some PAH at the high doses applied in rodent carcinogenicity tests. It is thus indicated that initiation and promotion are provoked by different chemical species: reactive metabolites and the parent hydrocarbons, respectively. At doses reflecting a normal human exposure situation the effects of initiation may be more important in the course of chemical carcinogenesis. The mechanisms of cancer initiation and cancer promotion should therefore be studied in more detail for reliable quantitative risk assessments.

Animals↗
PubMed1996

Stepwise comparative status analysis (STEP): a tool for identification of regional brain syndromes in dementia.

A method for clinical examination of patients with dementia, stepwise comparative status analysis (STEP), is presented. It combines psychiatric and neurologic status examination methods to identify certain common dementia symptoms by which the patient's regional brain symptom profile can be determined. Fifty status variables (items) are estimated with respect to occurrence and severity. The analysis is performed in three steps. The scores on the 'primary' variables reflect observations of single dementia symptoms. These scores form the basis for the assessment of the 'compound' variables, which in turn form the basis for evaluation of the 'complex' variables, one of which describes the patient's regional (predominant) brain syndrome (subcortical, frontosubcortical, frontal, frontoparietal, parietal, or global). In 96 mildly and moderately demented inpatients, the global (42%) and frontosubcortical (31%) were the most common. Ninety-one percent of the patients with vascular dementia had a predominant frontal and/or subcortical symptomatology.

Aged↗