Biomedical subjects

Maria Barcikowska

Publications and source records attributed to Maria Barcikowska.

14 recordsLinked to original sources

PubMed2011

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

ATP-Binding Cassette Transporters↗

PubMed2006

Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment.

Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes are associated with early-onset familial Alzheimer's disease (EOAD). There are several reports describing mutations in PSEN1 in cases with frontotemporal dementia (FTD). We identified two novel mutations in the PSEN1 gene: L226F and L424H. The first mutation was detected in a patient with a clinical diagnosis of FTD and a post-mortem diagnosis of AD. The second mutation is connected with a clinical phenotype of variant AD with strong FTD signs. In silico modeling revealed that the mutations, as well as mutations used for comparison (F177L and L424R), change the local structure, stability and/or properties of the transmembrane regions of the presenilin 1 protein (PS1). In contrast, a silent non-synonymous substitution F175S is eclipsed by external residues and has no influence on PS1 interfacial surface. We suggest that in silico analysis of PS1 substitutions can be used to characterize novel PSEN1 mutations, to discriminate between silent polymorphisms and a potential disease-causing mutation. We also propose that PSEN1 mutations should be considered in FTD patients with no MAPT mutations.

Adult↗

PubMed2005

CYP46: a risk factor for Alzheimer's disease or a coincidence?

Excess cholesterol is removed from the brain via hydroxylation mediated by cholesterol 24S-hydroxylase (CYP46). Although serum and cerebrospinal fluid (CSF) concentrations of 24S-hydroxycholesterol are altered during the progress of Alzheimer's disease, studies carried out to date in different populations on the association of CYP46 gene polymorphisms and risk of AD have been inconclusive. In this report, we analyzed CYP46 polymorphisms in 215 Polish AD cases and 173 healthy individuals. A fragment of CYP46 intron 2 was amplified by PCR reaction and sequenced. We discovered a new single nucleotide substitution in CYP46 intron 2, but found no difference in particular genotype or allele frequencies between AD patients and controls. However, the GG genotype of the known rs754203 polymorphic site might be a risk factor for AD, especially in APOE varepsilon4 carriers. Interestingly, in AD patients the rs754203 G allele was more frequent in males than in females. However, considering the extreme divergence of results obtained by different authors, a clear connection between the CYP46 gene and AD is questionable.

Aged↗

PubMed2005

[Alzheimer's disease therapy--theory and practice].

UNLABELLED: Alzheimer's disease (AD), a progressive degenerative disorder of the brain, affects a significant proportion of elderly population. The pharmacotherapy of AD is evolving rapidly. However, many doctors suggest the treatment which does not provide benefits in patients with the disease. The primary aim of this article was to review available data on the pathophysiologic background of AD and thus the most commonly used therapeutic agents, specifically cholinesterase-inhibitors (rivastigmine), Ginkgo biloba, piracetam and selegiline. Relevant double-blind, randomized, placebo-controlled studies were identified through a comprehensive search of Medline, NICE, Embase and CENTRAL databases. CONCLUSIONS: Only inhibitors of acetylcholinesterase are approved in mild and moderate stages of AD treatment. There is no evidence that Ginkgo biloba, selegiline, piracetam provide cognitive or behavioural improvement.

Alzheimer Disease↗

PubMed2004

The E318G substitution in PSEN1 gene is not connected with Alzheimer's disease in a large Polish cohort.

Mutations in the presenilin 1 (PSEN1) gene are known to cause nearly 50% of early-onset, familial Alzheimer's disease (AD) cases. To determine whether E318G mutation is related causally to AD in the Polish population E318G mutation frequency was assessed using PCR-RFLP method in a total of 659 subjects: 256 AD patients, 210 healthy, age-matched control subjects, 100 Parkinson's disease patients and 93 centenarians. When the mutation frequencies were compared to healthy controls, no significant differences between the groups were found. It could be concluded that E318G mutation is not related causally to AD in the Polish population, either as a risk factor or a disease causing mutation.

Aged↗

PubMed2004

New therapeutic approaches in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects a large proportion of the elderly population. It causes a progressive decline in memory and other cognitive functions. There is no effective treatment of AD despite the great effort in trying to find one. Herein new therapeutic approaches including those closely targeting the pathogenesis of the disease have been discussed. Potential disease modifying treatments that are being considered as future treatment of AD include avaccination, secretase inhibitors, cholesterol lowering drugs, metal chelators and anti- inflammatory agents. According to Evidence Based Dementia Practice, only inhibitors of acetylcholinesterase (AChE) are approved in mild and moderate stages of AD treatment. From the end of 2003, FDA also approved memantine for much severer phases of AD. When all the presented possibilities are taken into account, the most important target for scientists and physicians is not only to find ways for causative cure of AD, but also to be ready for that moment. There is a great need for finding routine biomarkers and sensitive enough clinical tests for diagnosis of AD in which the lasting pathological process does not destroy too many neurones.

Alzheimer Disease↗

PubMed2003

Strong association between Saitohin gene polymorphism and tau haplotype in the Polish population.

The saitohin (STH) gene is located in intron 9 of the tau protein gene. It has been postulated that the R allele of Q7R polymorphism at the Saitohin gene is over-represented in the homozygous state in sporadic Alzheimer's disease (AD). Tau protein was implicated in AD pathophysiology and the tau gene haplotype is probably connected with sporadic late-onset Parkinson's disease (PD). We analyzed the STH polymorphism and tau gene haplotype in 100 clinically diagnosed AD cases, 100 PD cases and 100 age-matched healthy controls. We found that the R allele of the STH gene is associated with the H2 haplotype of tau in all cases. Additionally we observed no correlation between R allele frequency and AD or PD.

Aged↗

PubMed2003

Simultaneous analysis of five genetic risk factors in Polish patients with Alzheimer's disease.

As Alzheimer's disease (AD) is a complex disease, we decided to estimate how previously reported genetic polymorphisms interact to increase the risk for the disease. Five candidate genes were chosen: apolipoprotein E (APOE), alpha 2-macroglobulin, cathepsin D, myeloperoxidase and nitric oxide synthase. Genotyping was performed in 100 cases of late-onset AD and 100 healthy controls. We found a highly significant difference in APOE epsilon 4 distribution between groups (P<0.005). However, no evidence of association for other studied loci was found. Cumulative analysis of five genetic polymorphisms was performed, but it also failed to reveal any synergistic effect of candidate genes greater than that caused by APOE itself. Our results suggest that the APOE epsilon 4 allele is the only known genetic risk factor for late-onset, sporadic AD.

Aged↗

PubMed2003

Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland.

Mutations in three causative genes have been identified in patients with an autosomal-dominant form of early-onset Alzheimer's disease (EOAD). To determine the spectrum of mutations in a group consisting of 40 Polish patients with clinically diagnosed familial EOAD and 1 patient with mild cognitive impairment (MCI) and family history of AD, we performed a screening for mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) genes. Four previously recognized pathogenic mutations in PSEN1 gene (H163R, M139V) and APP gene (T714A, V715A), and three novel putative mutations in PSEN1 gene (P117R and I213F) and PSEN2 gene (Q228L) were identified. The 34 patients with no mutations detected were older than the patients with mutations. A frequency of APOE4 allele was higher in this group. Frequency of mutations is relatively low (17%), possibly due to used operational definition of a patient with familial EOAD (a patient having at least one relative with early-onset dementia). It could be concluded that screening for mutations in the three genes could be included in a diagnostic program directed at patients with a positive family history or age of onset before 55 years.

Adult↗

PubMed2003

Mutation screening of the MAPT and STH genes in Polish patients with clinically diagnosed frontotemporal dementia.

Frontotemporal dementia (FTD) is a common neurodegenerative disorder and is connected with about 10% of all dementias. In approximately half of all FTD cases, a positive family history has been reported. To date, several mutations at the tau protein gene (MAPT) were identified causing familial and sporadic FTD. Extensive polymorphic variability at the MAPT gene has also been shown to be a risk factor in progressive supranuclear palsy (PSP). The recently described gene Saitohin (STH), located in the intron 9 of MAPT gene, was also reported to be polymorphic. In the present study 23 unrelated Polish patients with clinically defined sporadic and familial FTD were screened for mutations at the MAPT gene. No pathogenic mutations were found in the group. Several novel silent intronic and exonic mutations were identified, most of them associated with two common haplotypes. In the reported group no correlation between extended MAPT haplotype and APOE genotype was determined. There was also no observed relation between age of onset and APOE status. At the STH gene only a common polymorphic change was found. It is postulated that MAPT mutations are not connected with most of the FTD cases in the Polish population.

Aged↗

PubMed2002

Cognitive deficits and polymorphism of apolipoprotein E in Alzheimer's disease.

The aim of this study was to test the relationship between apolipoprotein E (ApoE) genotypes and patterns of cognitive deficits in Alzheimer's disease (AD). All subjects were diagnosed as probable AD patients on the basis of the DSM-IV and NINCDS-ADRDA criteria. Each subject was examined for (1) ApoE genotype, (2) general level of mental activity (Global Deterioration Scale and Mini-Mental State Examination) and (3) cognitive functions by means of a battery of neuropsychological tests. On the basis of ApoE genotype, patients were subdivided into two groups: the first group consisted of patients with at least one epsilon4 allele (epsilon4+ group), while the second one consisted of patients without the epsilon4 allele (epsilon4- group). Our results showed that several cognitive processes depended on the ApoE genotype. In early stages of AD, patients from the epsilon4+ group had greater deficits in delayed recall of new information. On the other hand, working memory appeared to be more impaired in the epsilon4- group of patients. Independent of the genotype, both groups showed similar impairment of learning ability without, however, deficits in remote memory.

Aged↗

PubMed2002

An open-label study to evaluate the safety, tolerability and efficacy of rivastigmine in patients with mild to moderate probable Alzheimer's disease in the community setting.

BACKGROUND: Long-term safety and efficacy of Exelon (rivastigmine) was evaluated in a multi-center open-label study of 62 patients with probable mild to moderate Alzheimer's disease living in community setting. MATERIAL/METHODS: The patients started treatment with 1.5 mg bid (3 mg/day) Exelon and were scheduled to receive doses of 1.5 mg bid Exelon escalating on a biweekly basis. The patients were maintained on the highest tolerated dose within the assigned dose range 1.5-6.0 mg bid (3-12 mg/day) for the rest of the study. Evaluations were scheduled at biweekly intervals for the first 8 weeks and subsequently at study weeks 12, 18 and 26. Effects of Exelon on cognition were evaluated using the mini-mental state examination (MMSE) and selected items of Alzheimer's disease assessment scale (ADAS-cog) and the staging of the disease was measured using the global deterioration scale (GDS). Safety was monitored by physical examinations, vital signs, laboratory tests, ECG recording and by the assessment of adverse events. RESULTS: 55 patients completed the study (89%). Patients treated for 26 weeks showed the mean MMSE, ADAS-cog and GDS scores close to baseline values (p=NS) with no improvement and no deterioration. Exelon was generally well tolerated with 11% of patients withdrawing due to adverse events. The most frequently reported adverse events related to the gastrointestinal tract. CONCLUSIONS: In conclusion, the study data indicate that treatment with Exelon is safe, generally well tolerated and inhibits the progression of cognitive decline in patients with mild to moderate Alzheimer's disease over 26 weeks of treatment.

Aged↗

PubMedDate not supplied

[Fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17): clinical criteria].

Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is a congenital degenerative disease of the central nervous system. Molecular genetics studies have indicated the presence of 26 various mutations of the tau protein gene. At present 61 families with this syndrome are known. The clinical criteria proposed in this paper were developed on the grounds of the author's own research as well as detailed review of the literature. The criteria include;--clinical symptoms: personality and behavior disorders, Parkinsonism rather resistant to treatment with Levodopa less frequently also speech disorders and epilepsy,--an early onset and rapid progression of the disease,--positive family history,--heterogeneity of clinical symptoms both among patients within the same family and among families with the same mutation,--heterogeneity of the clinical picture depending on the type of mutation. Although FTDP-17 is and extremely rare clinical syndrome, it is noted all over the world. In Poland nobody has been diagnosed with this condition yet. The aim of this paper is to acquaint the readers of Neurologia i Neurochirurgia Polska with the FTDP-17. The syndrome has considerably contributed to our understanding of pathogenesis of many sporadic degenerative diseases of the brain, including such frequent conditions as Alzheimer's disease, Pick's disease the the Steel-Richardson-Olszewski syndrome, corticobasal degeneration, and other ones. Undoubtedly further research into the FTDP-17 will contribute to the development of a successful treatment for these devastating degenerative diseases of the c.n.s.

Chromosomes, Human, Pair 17↗

PubMedDate not supplied

[Lactoferrin in the central nervous system].

Lactoferrin (LF) is a protein secreted by the tissues of ectodermal origin. Its structure is similar to transferrin. LF appeared to be multifunctional, but its main functions are connected with the natural defense system of mammals. The biological role and origin of LF within brain in normal and disease processes are as yet uncharted. LF expression is greatly upregulated during neurodegenerative disorders and in elderly brains. LF may exert an antiinflammatory function via its inhibitory effect on hydroxyl radical formation. By antioxydative properties, LF prevents DNA damage and consequently tumor formation in the CNS. Moreover, LF specifically transactivates the p53 tumor suppressor gene. LF suppresses distress perception via opioid mediated mechanism and prevents a decrease of the immune system activity caused by psychosocial stress. Furthermore, LF possibly modulates behavior in man and in animals.

Alzheimer Disease↗