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Biomedical subjects

L Lannfelt

Publications and source records attributed to L Lannfelt.

At least 19 recordsLinked to original sources
PubMed2006

New Alzheimer's disease locus on chromosome 8.

BACKGROUND: Family history is one of the most consistent risk factors for dementia. Therefore, analysis of families with a distinct inheritance pattern of disease can be a powerful approach for the identification of previously unknown disease genes. OBJECTIVE: To map susceptibility regions for Alzheimer's disease. METHODS: A complete genome scan with 369 microsatellite markers was carried out in 12 extended families collected in Sweden. Age at disease onset ranged from 53 to 78 years, but in 10 of the families there was at least one member with age at onset of < or =65 years. Mutations in known early-onset Alzheimer's disease susceptibility genes have been excluded. All people were genotyped for APOE, but no clear linkage with the epsilon4 allele was observed. RESULTS: Although no common disease locus could be found in all families, in two families an extended haplotype was identified on chromosome 8q shared by all affected members. In one of the families, a non-parametric multimarker logarithm of the odds (LOD) score of 4.2 (p = 0.004) was obtained and analysis based on a dominant model showed a parametric LOD score of 2.4 for this region. All six affected members of this family shared a haplotype of 10 markers spanning about 40 cM. Three affected members in another family also shared a haplotype in the same region. CONCLUSION: On the basis of our data, we propose the existence of a dominantly acting Alzheimer's disease susceptibility locus on chromosome 8.

Aged↗
PubMed2005

Consensus paper of the WFSBP Task Force on Biological Markers of Dementia: the role of CSF and blood analysis in the early and differential diagnosis of dementia.

Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Abeta peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.

Aged↗
PubMed2004

Unique physicochemical profile of beta-amyloid peptide variant Abeta1-40E22G protofibrils: conceivable neuropathogen in arctic mutant carriers.

A new early-onset form of Alzheimer's disease (AD) was described recently where a point mutation was discovered in codon 693 of the beta-amyloid (Abeta) precursor protein gene, the Arctic mutation. The mutation translates into a single amino acid substitution, glutamic acid-->glycine, in position 22 of the Abeta peptide. The mutation carriers have lower plasma levels of Abeta than normal, while in vitro studies show that Abeta1-40E22G protofibril formation is significantly enhanced. We have explored the nature of the Abeta1-40E22G peptide in more detail, in particular the protofibrils. Using size-exclusion chromatography (SEC) and circular dichroism spectroscopy (CD) kinetic and secondary structural characteristics were compared with other Abeta1-40 peptides and the Abeta12-28 fragment, all having single amino acid substitutions in position 22. We have found that Abeta1-40E22G protofibrils are a group of comparatively stabile beta-sheet-containing oligomers with a heterogeneous size distribution, ranging from >100 kDa to >3000 kDa. Small Abeta1-40E22G protofibrils are generated about 400 times faster than large ones. Salt promotes their formation, which significantly exceeds all the other peptides studied here, including the Dutch mutation Abeta1-40E22Q. Position 22 substitutions had significant effects on aggregation kinetics of Abeta1-40 and in Abeta12-28, although the qualitative aspects of the effects differed between the native peptide and the fragment, as no protofibrils were formed by the fragments. The rank order of protofibril formation of Abeta1-40 and its variants was the same as the rank order of the length of the nucleation/lag phase of the Abeta12-28 fragments, E22V>E22A?E22G>E22Q?E22, and correlated with the degree of hydrophobicity of the position 22 substituent. The molecular mass of peptide monomers and protofibrils were estimated better in SEC studies using linear rather than globular calibration standards. The characteristics of the Abeta1-40E22G suggest an important role for the peptide in the neuropathogenesis in the Arctic form of AD.

Alzheimer Disease↗
PubMed2002

Conversion from preclinical to dinical stage of Alzheimer's disease as shown by decline of cognitive function in carriers of the Swedish APP-mutation.

The characterisation of the borderline syndrome between normal cognitive function and Alzheimer's disease (AD), often mentioned as Mild Cognitive Impairment (MCI) has been a goal for recent research. However, a variety of definitions of MCI-like syndromes and the uncertainty about the final diagnosis have hampered progress. To overcome these problems, the present study will describe cognitive function in two healthy mutation carriers and two matched non-carriers of the Swedish double mutation family, during the time period when carriers convert to a symptomatic stage, i.e., true preclinical AD, and finally into the stage when a clinical diagnosis of AD is first possible. The findings question the generality of common MCI concepts and the commonly held beliefs about cognitive features in late preclinical stage of AD.

Alzheimer Disease↗
PubMed2002

APOE genotypes and disease severity in multiple sclerosis.

Apolipoprotein E (opoE) is involved in the transport of lipids necessary for membrane repair and is encoded by a gene on chromosome 19q13, a region positive for linkage in two multiple sclerosis (MS) genome-wide screens. The APOE epsilon4 allele confers susceptibility to both familial and sporadic Alzheimer's disease (AD). Carriage of epsilon4 is associated with defective dendritic remodeling in AD, and with unfavorable clinical outcome in head trauma and cerebrovascular disease. According to the results of previous studies, APOE epsilon4 does not increase the risk of developing MS, but it may influence disease progression and ultimate disability. From a total cohort of over 900 MS patients, we compared APOE epsilon2-4 genotypes in, roughly, the cohort's least disabled and most disabled septiles. 'Benign MS' (n=124) was defined as an Expanded Disability Status Scale (EDSS) score of 3.0 or less, despite at least 10 years of disease duration, and 'severe MS' (n=140) as the attainment of an EDSS score of 6.0 within 8 years of disease onset. We found no significant differences in genotype or phenotype frequencies between the benign-MS and severe-MS septiles; however, the risk conferred by epsilon4 rose progressively upon comparison of carriage rates in more narrowly defined anti-podal quantiles.

Adolescent↗
PubMed2001

On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells.

Evidence is accumulating for a link between cerebral cholesterol metabolism and Alzheimer's disease (AD). Here we focus on a possible relationship between AD and a newly discovered mechanism for cholesterol efflux from the brain, involving conversion of brain cholesterol into 24S-hydroxycholesterol by the neuronal oxidative enzyme CYP46. There was a marked difference in the distribution of CYP46 in brains of control and AD patients. The neuronal cells were less stained in AD brains than in controls while marked positive staining was found in glial cells in AD but not in controls. The dynamic changes in the mechanisms for cholesterol efflux from the brain are of interest in relation to the link between brain cholesterol and amyloid beta-protein in AD.

Aged↗
PubMed2001

Increased risk for frontotemporal dementia through interaction between tau polymorphisms and apolipoprotein E epsilon4.

The tau gene has an important role in frontotemporal dementia (FTD) as pathogenic mutations have been found in hereditary forms of the disease. Furthermore, a certain extended tau haplotype has been shown to increase the risk for progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease and, in interaction with the apolipoprotein E (apoE) epsilon4 allele, Alzheimer's disease. By microsatellite analysis we investigated an intronic tau polymorphism, in linkage disequilibrium with the extended tau haplotype, in FTD patients (n = 36) and healthy controls (n = 39). No association between any of the tau alleles/genotypes and FTD was seen, but certain tau alleles and apoE epsilon4 interactively increased the risk of FTD (p = 0.006). We thus propose that this extended tau haplotype in combination with apoE epsilon4 is a genetic risk factor for FTD.

Aged↗
PubMed2001

Apolipoprotein E genotypes and the incidence of Alzheimer's disease among persons aged 75 years and older: variation by use of antihypertensive medication?

The authors examined the impact of the apolipoprotein E (APOE)(*)epsilon4 allele on Alzheimer's disease incidence in relation to use of antihypertensive medication. A population-based (Kungsholmen Project) cohort of 985 nondemented Swedish subjects aged >/=75 years was followed for an average of 3 years (1990-1992); 164 dementia (122 Alzheimer's disease) cases were identified. Compared with (*)epsilon3/(*)epsilon3, the APOE(*)epsilon4 allele increased the risk of developing dementia (relative risk (RR) = 1.5, 95% confidence interval (CI): 1.1, 2.1) and Alzheimer's disease (RR = 1.7, 95% CI: 1.2, 2.5). Subjects using antihypertensive medication at baseline (n = 432, 80% used diuretics) had a decreased risk of dementia (RR = 0.6, 95% CI: 0.5, 0.9) and Alzheimer's disease (RR = 0.5, 95% CI: 0.3, 0.8) after adjustment for several variables, including APOE. The effect of antihypertensive medication use was more pronounced among (*)epsilon4 carriers. For those not using antihypertensive medication, the relative risks of dementia and Alzheimer's disease for carriers were 2.2 (95% CI: 1.4, 3.4) and 2.3 (95% CI: 1.4, 3.7), respectively. The corresponding relative risks for those using antihypertensive medication were 0.9 (95% CI: 0.5, 1.6) and 1.1 (95% CI: 0.6, 2.2). The APOE(*)epsilon4 allele is an important predictor of dementia and Alzheimer's disease incidence. Further studies are needed to clarify whether use of antihypertensive medication, especially diuretics, modifies the effect of the allele.

Age Factors↗
PubMed2001

Clinic-based cases with frontotemporal dementia show increased cerebrospinal fluid tau and high apolipoprotein E epsilon4 frequency, but no tau gene mutations.

Frontotemporal dementia (FTD) belongs to a group of neurodegenerative disorders known as tauopathies, characterized by intracellular aggregation of hyperphosphorylated tau protein in the brain. Some tauopathies, like Alzheimer's disease (AD), consistently show increased levels of tau protein in cerebrospinal fluid (CSF). However, similar studies in FTD populations have shown variable results, although mutations in the tau gene are identified as causes of disease in certain FTD families. In the present study, a Swedish clinic-based FTD population was investigated with respect to CSF tau levels, apolipoprotein E (APOE) genotype distribution and occurrence of mutations in the tau gene. CSF tau levels were significantly increased among FTD patients (534 +/- 235 pg tau/ml, P < 0.001) (n = 47) compared to controls (316 +/- 137 pg tau/ml) (n = 51). Furthermore, a strong increase in the APOE epsilon4 allele frequency was found in the FTD population, as 52% were epsilon4 carriers, compared to 21% of the controls. However, no mutations in the tau gene were identified. These findings support the present notion of a common pathogenic pathway in the disease processes for several tauopathies, with both APOE epsilon4 and CSF tau being a pathological link between the different disorders. Furthermore, we conclude that mutations in the tau gene are a rare cause of FTD. .

Aged↗
PubMed2001

The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation.

Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid beta-protein (Abeta) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the Abeta sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased Abeta42 and Abeta40 levels in plasma. Additionally, low levels of Abeta42 were detected in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated no difference in fibrillization rate, but Abeta with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) Abeta. The finding of increased protofibril formation and decreased Abeta plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid Abeta protofibril formation leading to accelerated buildup of insoluble Abeta intra- and/or extracellularly.

Alzheimer Disease↗
PubMed2001

Investigations of a CA repeat in the oestrogen receptor beta gene in patients with Alzheimer's disease.

Several studies have shown that oestrogen treatment after menopause decreases the risk for Alzheimer's disease (AD). It is also known that oestrogen stimulates the outgrowth of nerve cells and that apolipoprotein E (Apo E) synthesis and amyloid precursor protein (APP) metabolism are regulated by oestrogen. Recently a new oestrogen receptor was identified, oestrogen receptor beta (ERbeta), located at chromosome 14q22-24. Several genes close to this chromosomal region have been implicated in AD, but the results are conflicting. Our hypothesis was that variations in the ERbeta gene could be the underlying cause to the positive findings in these genes and we have therefore investigated a CA repeat(1) in intron 5 of the ERbeta gene. Three hundred and thirty-six AD cases and 110 healthy age-matched controls were included in this study. Fourteen different alleles were found with frequencies between 0.1 and 37%. There was no significant difference between AD cases and controls when all alleles were compared. However, allele 5 was seen in 13.6% of the controls but only in 8.0% of AD cases (P=0.014; odds ratio (OR)=0.55). No AD patient homozygous for this allele was seen but three controls were homozygous. In conclusion, our findings suggest the ERbeta allele 5 to be a protective factor. However, this has to be confirmed in a larger population.

Aged↗
PubMed2000

Tau protein in cerebrospinal fluid from semantic dementia patients.

Apolipoprotein E (APOE) genotypes and cerebrospinal fluid (CSF) tau protein concentration were evaluated in patients suffering from semantic dementia, with the aim of determining whether these markers could help to differentiate this condition from Alzheimer's disease (AD) in early stages. By strictly following diagnostic criteria for semantic dementia, we found a clinically homogeneous group comprising eight patients from a total population of 621 subjects referred for dementia investigation. CSF tau protein concentrations were moderately increased with a small intraindividual variation 437+/-36 pg/ml (mean+/-SD) compared to healthy control individuals. APOE genotype distribution showed an over representation of the epsilon4 allele (69% epsilon3, 31% epsilon4 and no epsilon2), a pattern similar to that found in AD. These results indicate that semantic dementia is a rather uncommon but clinically distinct condition which shows a moderate increase of CSF tau protein levels and for which the epsilon4 allele is a risk factor.

Alzheimer Disease↗
PubMed2000

Interaction between estrogen receptor 1 and the epsilon4 allele of apolipoprotein E increases the risk of familial Alzheimer's disease in women.

Estrogens may be implicated in the development of Alzheimer's disease (AD). Most of their effects are mediated via receptors whose function and expression may be modified by DNA polymorphisms. Here the estrogen receptor 1 gene (ESR1) polymorphisms XbaI and PvuII were analyzed in 214 AD patients and 290 controls. In logistic regression analysis, a significantly increased risk of familial AD due to interaction between the ESR1 xx genotype and the apolipoprotein E epsilon4 allele was observed in women in a Swedish clinic-based sample, taking subjects who had neither the xx genotype nor epsilon4 as reference (OR 11.3, 95% CI 2.9-43.8). The risk of AD was more pronounced in early-onset (OR 22.0, 95% CI 3. 7-132.7) than in late-onset (OR 6.0, 95% CI 1.2-29.7) female patients. For women carrying the pp genotype together with epsilon4 the risk of AD was similarly elevated. Likewise in a Swedish community-based set of women, an increased risk of familial AD was observed in subjects who had either the ESR1 xx or pp genotype together with epsilon4. Furthermore, the Pp genotype frequency was found to be significantly increased in Finnish women with sporadic AD. We, thus, conclude that the ESR1 gene may have a role in the development of AD in females.

Age of Onset↗
PubMed2000

Amyloid Abeta40 CSF concentrations correlate to frontal lobe atrophy in frontotemporal dementia.

We wanted to further study amyloid Abeta protein alterations in non-AD neurodegenerative diseases. Cerebrospinal fluid concentrations of the amyloid Abeta protein with 40 (Abeta40) and 42 (Abeta42) amino acid residues were measured in eleven patients with frontotemporal dementia (FTD). Abeta40 and Abeta42 concentrations were related to the degree of frontal lobe atrophy as assessed with MRI volumetry. Abeta40 concentrations showed a statistically significant linear correlation with degree of frontal lobe atrophy (r = -0.77, p<0.02). Similar results have not been found in previous studies of CSF Abeta40 concentrations and atrophy in patients with AD which suggest that the role of Abeta40 differs between the pathological processes of FTD and AD.

Aged↗
PubMed2000

Genetics of Alzheimer's disease--routes to the pathophysiology.

Considerable advances have been made the last years in the understanding of the pathogenesis of Alzheimer's disease (AD): Several pathogenic mutations have been found in the amyloid precursor protein gene on chromosome 21. Two other dominantly operating genes on chromosome 14 and 1 were recently cloned, named presenilin 1 and 2, respectively. Mutations in these genes give rise to AD with a very early age of onset. Increased Abeta1-42 is most likely the pathogenic mechanism in all these cases. A susceptibility gene for AD has also been found. There is an association between the epsilon4 allele of the apolipoprotein E (APOE) gene and late-onset AD. The epsilon4 allele increases the risk for AD, although some epsilon4 homozygotes may live a long life without developing AD. The mechanism by which APOE epsilon4 promotes development of AD is most likely increased plaque formation. The new knowledge on pathogenic mechanisms of the disease gives opportunities for alternative strategies for therapeutic intervention.

Alzheimer Disease↗
PubMed2000

Histamine H2 receptor gene variants: lack of association with schizophrenia.

A role of histaminergic neuronal systems in schizophrenia was suggested by an association with several polymorphisms located in the coding region of the histamine H2-receptor (H2R) gene (Orange et al, Mol Psychiatry 1996; 1: 466-469). Using either the reference method of direct sequencing or restriction endonuclease digestion of PCR products amplified from DNA, we could not confirm the existence of these polymorphisms in 53 Swedish controls, 52 French controls and 88 French schizophrenics. In contrast, we detected a G543A transition in the coding region of the gene that was not found in the British population. This allelic variation, which was observed in 15% of the controls with no homozygotes, did not change the amino acid sequence of the receptor. We also analyzed a 1.8-kb nucleotide sequence of the promoter region in which we detected two additional polymorphisms that may modulate the expression of the H2R gene. The first one was a A-592G transition located in the minimal promoter of the gene and found in;10% of controls with no homozygotes. The second one was a G-1018A transition located in an enhancer element of the promoter and was found in;20-30% of controls (with;2-4% homozygotes). DNA analysis of the 88 French schizophrenic subjects revealed that the incidence of the three polymorphisms was not significantly different in this population. In conclusion, the present findings may suggest a surprisingly high variability of the H2R gene polymorphisms in different geographical areas but do not support an association of these allelic variations with schizophrenia.

Female↗