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Late-onset Alzheimer’s disease (LOAD) is the most common neurodegenerative disorder, and has a complex etiology. Recently an intronic polymorphism in the ubiquilin 1 gene (UBQLN1) and a particular haplotype was reported to be associated with LOAD. We investigated whether variants in UBQLN1 confer a risk for the disease in 407 Polish LOAD patients and 407 controls. We observed a weak association with the rs2781002 polymorphism, however, contrary to the initial reports, in our group the association was with the A allele. Risk estimation for AA versus GG genotypes showed that the AA genotype is a weak risk factor for AD (OR = 1.8, 95% CI = 1.1–3.1, p = 0.025). This effect was stronger in a group of LOAD patients without APOE4 allele. Haplotype analyses indicate that there is an increase of haplotypes with an A allele in the case group. Also, the specific haplotypes with the A allele that increase AD risk differ between the APOE4-positive and APOE4-negative pools. However, the association observed seems to be driven mostly by rare (UBQLN1 locus.

Presenilin 2 gene (PSEN2) is one of the causative genes for familial Alzheimer's disease. A delA polymorphism located in PSEN2 promoter was proposed to be a risk factor for early-onset AD. We examined association between AD and PSEN2 polymorphisms located in two 5'UTR regions in group of 217 late-onset AD patients, 109 mild cognitive impairment patients, and 225 non-demented control subjects. No significant differences for genotype and allele distributions of a delA and a novel insAC polymorphisms in the studied groups as compared to controls were observed. Univariate and multivariate risk estimation shows that neither delA, insAC alleles nor the genotypes are risk factors for AD. No significant interaction between the APOE4 and PSEN2 polymorphisms was found. A bioinformatic analysis showed that delA polymorphism influences binding sites of transcription factors involved in the cellular processes related to AD. The rare variants identified in exon 3 of the PSEN2 could have a potential influence on PSEN2 transcript splicing.

A 32-year-old woman diagnosed with very rapidly progressing early-onset Alzheimer's disease (EOAD), age of onset 29 years, and S170F mutation in presenilin 1 gene (PSEN1) is presented. Neuroimaging conducted 2 years after the first symptoms was typical for the advanced stage of Alzheimer's disease (AD), showing cortical brain atrophy, particularly within hippocampus, frontal and temporal cortex. The unaffected parents of the proband are not carriers of the mutation. The paternity was confirmed by microsatellite typing, strongly suggesting de novo origin of S170F mutation. In silico modeling of S170F mutation impact on presenilin 1 (PS1) transmembrane structure indicates that the mutation considerably alters putative interactions of PS1 with other proteins within gamma-secretase complex.

Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome are classified as transmissible cerebral amyloidoses, in contrast to the non-transmissible amyloidoses of Alzheimer's disease type. While the aetiologies of Creutzfeldt-Jakob disease and Alzheimer's disease and the molecular composition of their amyloids are different, similar basic pathogenetic mechanisms operate in both diseases through synthesis and processing of amyloid precursor proteins, to produce an accumulation of amyloid deposits. We report here a case of Creutzfeldt-Jakob disease exhibiting numerous diffuse A beta immunoreactive plaques, thus presenting features of both Creutzfeldt-Jakob disease and Alzheimer's disease. The existence of such cases underlines the existence of a 'grey' area between the two types of amyloidoses.

Objective The aim of this study was to evaluate the cognitive state of highly selected Polish centenarians and analyze the mechanisms of their functioning. Methods The selected centenarian group (10 persons) and a reference group (20 persons) who started aging (65 years) were examined with a sensitive set of neuropsychological tests and tasks in clinical-experimental assessment. Results As expected, the centenarians' cognitive functions were different from those of the subjects who started aging, however, not in all aspects. For instance, the former scored significantly lower in the area of linguistic functions but the ability to plan and controlled perform complex visuospatial task with use of simultaneous and sequential strategies was preserved despite unfavorable symptoms of natural aging such as permanence attention as well as prolonged action time. Conclusions The results suggest that the studied centenarians show a dominant right-hemispheric pattern functioning not only in relation to perception, but also to planning and executing complex activities. The study and description of preserved neurocognition of centenarians was possible due to introducing a special procedure sensitive to the preserved functions. Copyright © 2007 John Wiley & Sons, Ltd.

Objective: To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies. Methods: In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls. Results: The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63-2.98, p 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62-20.51, p 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04-12.17, p 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85-25.72, p 0.08) but this was not statistically significant and therefore should be interpreted with caution. Conclusions: Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies. © 2015 American Academy of Neurology.

Introduction Mild cognitive impairment (MCI) is defined as abnormal cognitive state, but does not meet the criteria for the diagnosis of dementia. According to the new guidelines Alzheimer's disease (AD) involves not only dementia's phase but also predementia phase which is asymptomatic and pathological process in the brain is already present. For this reason it is very important to determine the suitability of markers which should be positive before onset of the first symptoms. One of these biomarkers is a structural magnetic resonance imaging with hippocampal volumetric assessment. The aim of this study was to investigate the usefulness of structural brain magnetic resonance imaging with volumetric assessment of the hippocampus and entorhinal cortex, posterior cingulate gyrus, parahippocampal gyrus, temporal gyri: superior, medial and inferior, to predict the conversion of MCI to AD. Material and methods Magnetic resonance imaging of brain was performed at the baseline visit in 101 patients diagnosed with MCI. Clinic follow-ups were scheduled after 6.12 and 24 months. Results Amongst 101 patients with MCI, 17 (16.8%) converted into AD within two years of observation. All measured volumes were lower in converters than non-converters. Discriminant analysis was conducted and sensitivity for MCI conversion to AD was 64.7%, specificity 96.4%. 91% of patients were correctly classified (converter or non-converter). Conclusions Volumetric measurements may help clinicians to predict MCI conversion to AD but due to low sensitivity it cannot be use separately. The study group requires further observation.

BackgroundRecently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi-incident Mennonite family. MethodsIn the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD). ResultsOur sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed. ConclusionOur results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.

Objective: To assess the role of CHCHD2 variants in patients with Parkinson disease (PD) and Lewy body disease (LBD) in Caucasian populations. Methods: All exons of the CHCHD2 gene were sequenced in a US Caucasian patient-control series (878 PD, 610 LBD, and 717 controls). Subsequently, exons 1 and 2 were sequenced in an Irish series (355 PD and 365 controls) and a Polish series (394 PD and 350 controls). Immunohistochemistry and immunofluorescence studies were performed on pathologic LBD cases with rare CHCHD2 variants. Results: We identified 9 rare exonic variants of unknown significance. These variants were more frequent in the combined group of PD and LBD patients compared to controls (0.6% vs 0.1%, p = 0.013). In addition, the presence of any rare variant was more common in patients with LBD (2.5% vs 1.0%, p = 0.050) compared to controls. Eight of these 9 variants were located within the gene9s mitochondrial targeting sequence. Conclusions: Although the role of variants of the CHCHD2 gene in PD and LBD remains to be further elucidated, the rare variants in the mitochondrial targeting sequence may be a risk factor for Lewy body disorders, which may link CHCHD2 to other genetic forms of parkinsonism with mitochondrial dysfunction.

Elevated levels of homocysteine have been observed in Parkinson's disease (PD) patients treated with levodopa. However, it is not studied if duration of PD or PD per se is associated with hyperhomocysteinemia. In the present study, the levels of homocysteine in 99 levodopa-treated PD patients, 15 untreated PD patients and 100 controls were examined. We focused on the influence of levodopa dose, duration of therapy and disease as well as genetic (C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism) and environmental factors. We found that levodopa-treated PD patients had elevated homocysteine plasma levels as compared to controls (p < 0.05), but the levels did not depend on levodopa doses. Another factor influencing homocysteine level was the duration of PD (p < 0.001). The frequency of allele C677T of MTHFR gene did not differ between PD and controls. In conclusion, hyperhomocysteinemia is associated with the duration of PD and levodopa treatment and possibly also with PD per se.

The -22c/t polymorphism in the promoter of the presenilin 1 gene is associated with increased risk for Alzheimer's disease (AD) in some populations. It was shown that -22c allele is connected with two-fold decrease in promoter activity. We studied the impact of the polymorphism in groups of Polish late-onset and early-onset AD patients. Our results suggest that -22c/t polymorphism is not connected with AD in Polish population. The -22t allele showed a high degree of linkage disequilibrium with -2797 insertion of 13 bp. An additional -2923g/t polymorphism is also not connected with -22c/t and is not a risk factor for AD.

The importance of apolipoprotein E (ApoE) and myeloperoxidase (MPO) genotypes in the clinical characteristics of multiple sclerosis (MS) has been recently emphasized. In a large group of Polish patients we have tested the hypothesis that polymorphism in ApoE and MPO genes may influence the course of the disease. G enotypes were determined in 117 MS patients (74 females and 43 males; 99 sporadic and 18 familial cases) with mean EDSS of 3.6, mean age of 44.1 years, mean duration of the disease 12.8 years and mean onset of MS at 31.2 years, and in 100 healthy controls. The relationship between ApoE and MPO genes’ polymorphism and the MS activity as well as the defect of remyelination (diffuse demyelination) and brain atrophy on MRI were analysed. The ApoE o4 allele was not related to the disease course or the ApoE o2 to the intensity of demyelination on MRI. The genotype MPO G/G was found in all familial MS and in 57% (56/99) of sporadic cases. This genotype was also related to more pronounced brain atrophy on MRI. The MPO G/G subpopulation was characterized by a significantly higher proportion of patients with secondary progressive MS (PB- 0.05) and by a higher value of EDSS. A ccording to our results the MPO G allele is frequently found (in 96% of cases) among Polish patients with MS. More severe nervous tissue damage in the MPO G/G form can be explained by the mechanism of accelerated oxidative stress. It seems that MPO G/G genotype may be one of the genetic factors influencing the progression rate of disability in MS patients.

Objective The aim of the study was to detect the prevalence of depressive syndromes and symptoms in the sample of elderly persons with Mild Cognitive Impairment (MCI), and to analyse Montgomery-Asberg Depression Rating (MADRS) item scores. Method The subjects of the study were 102 consecutive out-patients with MCI. All subjects were assessed by an experienced psychiatrist and MADRS was applied. Major and minor depressive episodes were defined according to DSM-IV criteria. Factor analysis was used to analyse baseline MADRS item scores. Results Three patient groups emerged according to the depressive symptoms distribution and severity scores basis: those with major depression constituted 19.6% (n = 20), with minor depression 26.5% (n = 27), and with very few depressive symptoms 53.9% (n = 55). Three interpretable MADRS factors were identified, using the factor analysis with Varimax rotation: the first consisting of apparent and reported sadness, inability to feel, pessimistic thoughts, the second consisting of inner tension, reduced sleep, reduced appetite, suicidal thoughts, and the third with concentration difficulties and lassitude. Conclusions It was concluded that both major and minor depression is common in MCI. Three MADRS factors were identified and labelled as anhedonia-pessimism, anxiety-vegetative, and cognitive-inhibition. Copyright © 2004 John Wiley & Sons, Ltd.

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.

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.

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 Ε4 allele (Ε4+ group), while the second one consisted of patients without the Ε4 allele (Ε4– group). Our results showed that several cognitive processes depended on the ApoE genotype. In early stages of AD, patients from the Ε4+ group had greater deficits in delayed recall of new information. On the other hand, working memory appeared to be more impaired in the Ε4– group of patients. Independent of the genotype, both groups showed similar impairment of learning ability without, however, deficits in remote memory.

The aim of this study was to define the co-occurrence of behavioural symptoms and Alzheimer’s disease (AD) in relation to apolipoprotein E (APOE) genotype. Probable AD patients from the Alzheimer’s Day Clinic (n = 139) were assessed with the ‘Behavioural Pathology in Alzheimer’s Disease’ rating scale, and their APOE genotype was determined. This study demonstrated no relationship between presence of the APOE Ε4 allele and any of the behavioural symptoms assessed, including delusions, hallucinations, depression, activity disturbances, aggressiveness and anxiety. Activity disturbances, delusions, hallucinations and aggressiveness paralleled the severity of AD, increasing in frequency with the severity of the dementia. The prevalence of delusions, hallucinations, aggressiveness and depression were found to be associated with lower levels of education.

Genome-wide association studies (GWAS) in Parkinson’s disease (PD) have identified over 20 genomic regions associated with disease risk. Many of these loci include several candidate genes making it difficult to pinpoint the causal gene. The locus on chromosome 2q24.3 encompasses three genes: B3GALT1, STK39, and CERS6. In order to identify if the causal variants are simple missense changes, we sequenced all 31 exons of these three genes in 187 patients with PD. We identified 13 exonic variants including four non-synonymous and three insertion/deletion variants (indels). These non-synonymous variants and rs2102808, the GWAS tag SNP, were genotyped in three independent series consisting of a total of 1976 patients and 1596 controls. Our results show that the seven identified 2q24.3 coding variants are not independently responsible for the GWAS association signal at the locus; however, there is a haplotype, which contains both rs2102808 and a STK39 exon 1 6bp indel variant, that is significantly associated with PD risk (Odds Ratio [OR] = 1.35, 95% CI: 1.11–1.64, P = 0.003). This haplotype is more associated than each of the two variants independently (OR = 1.23, P = 0.005 and 1.10, P = 0.10, respectively). Our findings suggest that the risk variant is likely located in a non-coding region. Additional sequencing of the locus including promoter and regulatory regions will be needed to pinpoint the association at this locus that leads to an increased risk to PD.

We recently showed that mutation of the VPS35 gene can cause late-onset Parkinson’s disease. In the present study we sequenced 702 affected subjects from the Mayo Clinic Parkinson’s disease patient-control series for the VPS29 and VPS26A/B genes. We identified only two rare non-synonymous variants in the VPS26A p.K93E and VPS29 p.N72H. The results show that mutations in the genes composing the retromer cargo recognition subunit are not a common cause of Parkinson’s disease.

Objectives: Patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) may be agraphic. The study aimed at characterizing agraphia in individuals with a P301L MAPT mutation.Methods: Two pairs of siblings with FTDP-17 were longitudinally examined for agraphia in relation to language and cognitive deficits.Results: All patients presented with dysexecutive agraphia. In addition, in the first pair of siblings one sibling demonstrated spatial agraphia with less pronounced allographic agraphia and the other sibling had aphasic agraphia. Aphasic agraphia was also present in one sibling from the second pair.Conclusion: Agraphia associated with FTDP-17 is very heterogeneous.

The aim of our study was to analyze EEG changes in patients with Alzheimer disease (AD) and to determine how closely EEG reflects the progression of mental impairment in people with AD. Ninety-five patients with probable AD according to National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria treated in our Clinic for Memory Disorders were selected for this study. Patients were divided into three subgroups with mild, marked, and severe dementia according to the results of psychometric scales. The EEG findings were classified using an eight-degree scale according to the background activity, presence and amount of theta and delta waves, focal changes, lateralization of focal changes, synchronization, and presence of sharp and spike waves. A significant correlation between the degree of EEG abnormalities and cognitive impairment was found. We did not observe any correlation between the presence of delta waves and the results of neuropsychological tests. Our study revealed an important diagnostic value of EEG in the estimation of the severity of dementia parallel to psychometric scales.

The clinical recognition of frontotemporal dementia (FTD) depends on its differentiation from Alzheimer’s disease (AD). From 212 patients primarily diagnosed as probable AD, 24 cases with mild dementia, absence of disturbances the presence of which would have prevented a full neuropsychological assessment, and brain CT with detailed visualization of hippocampus atrophy were chosen. On the basis of neuropsychological examination the patients were divided into two groups: 11 cases with predominant deficit in frontal system tasks (FTD group) and 13 cases with changes in cognitive functions typical of AD (AD group). Age at onset, duration, behavioral changes, psychotic symptoms, depression, speech disorders, neurologic deficit and hippocampal atrophy were analyzed in both groups. Statistically significant differences for behavioral disturbances and hippocampal atrophy were found. Early behavioral changes and lack of early hippocampal atrophy on CT may be useful features for differentiating between FTD and AD, especially when SPECT is not available.

The accumulation of beta-amyloid (Abeta) in the brain plays a central role in the pathogenesis of Alzheimer's disease (AD). The processing of Abeta precursor protein to Abeta is modulated by binding proteins including APBB2 [amyloid beta precursor protein-binding family B member 2, FE65-like, FE65L1]. We investigated two intronic SNPs within the APBB2 gene: rs13133980 and hCV1558625 (rs17443013), among Polish AD patients and healthy controls (n=213, 171). The frequencies of rs13133980 alleles and genotypes did not differ between cases and controls, irrespective of age of onset or APOE epsilon4 carrier status. The hCV1558625 G allele was over-represented in patients with onset under age 70 compared to controls in the same age range (57% vs. 43%, p=0.03). The association between the hCV1558625 G allele and susceptibility for AD at relatively young ages needs to be confirmed in other samples.

We observed in extra- and intracellular space accumulation of different fragments of amyloid precursor protein (APP) and apolipoprotein E (Apo E) in rat brain after cardiac arrest with long-term survival. Idebenone treatment did not affect APP and Apo E alterations in this condition.

Matrix metalloproteinases (MMPs) and their natural tissue inhibitors (TIMPs) are involved in cell signaling processes and the release of extracellular matrix (ECM) and non-ECM molecules. Nonregulated MMP activity and an imbalance between metalloproteinases and their inhibitors might contribute to various disorders, including neurodegenerative diseases such as Alzheimer's disease (AD), which is the most common cause of dementia. There is a complex relationship between MMPs and TIMPs with AD. It has been shown that MMPs and TIMPs are localized in neuritic senile plaques and neurofibrillary tangles in the postmortem brains of patients with AD. Some MMPs have also been shown to induce tau aggregation and the formation of neurofibrillary tangles in vitro. Moreover, MMPs contribute to AD pathogenesis via the disruption of the blood-brain barrier and promotion of neurodegeneration. However, MMPs can degrade both soluble and fibrillar forms of amyloid-β (Aβ). It has also been shown that Aβ enhances the expression of MMPs in neuroglial cultures and induces the release of TIMP-1 by brain cells. Inhibition of Aβ-induced MMP activity resulted in an improvement of performance tests in mice. Moreover, simultaneous examination of MMP-9, MMP-2, and TIMP-1 in the CSF contributed to the ability to differentiate between AD and other types of dementia. Thus, the aim of this literature study was to describe the role of MMPs and TIMPs in neurodegeneration, as well as their potential usefulness as CSF or plasma biomarkers in the diagnosis of AD as well as other neurodegenerative disorders and vascular dementia.

Background A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders. Results The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed. Conclusions Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.

Brains from patients with Alzheimer's disease contain amyloid plaques which are composed of beta-amyloid peptide and are considered to play a causal role in the neuropathology of this disease. The origin of beta-amyloid peptide in brain parenchyma and vessels of Alzheimer's disease patients is not known. This study examined the permeability of the blood-brain barrier to beta-amyloid peptide in rats subjected to single or repeated episodes of global cerebral ischaemia followed by i.v. injections of human synthetic beta-amyloid-(1-42)-peptide. Rats receiving beta-amyloid peptide after ischaemia demonstrated multifocal and widespread accumulation of beta-amyloid peptide in hippocampus, cerebral cortex and occasionally in white matter. beta-Amyloid peptide penetration involved arterioles, veins and venules. Neuronal, glial and pericyte bodies were observed filled with beta-amyloid peptide. Direct evidence that soluble human beta-amyloid-(1-42)-peptide crosses the blood-brain barrier and enters the brain from the circulation is thus provided for the first time.

The authors present a study on the association of PRNP and PRND gene polymorphisms with the occurrence and age at onset of Alzheimer's disease (AD). DNA from 79 Polish patients with probable AD and 107 healthy control subjects was studied. The PRNP codon 129 homozygosity seemed to be associated with the occurrence of AD: In AD patients, the percentage of Val/Val and Met/Met genotypes was higher than in the control subjects. A significant difference appeared also between early-onset (70 years) and late-onset (or = 70 years) AD patients in the PRND genotypes.

Polymorphic, deoxythymidine-tract in intron 6 of the TOMM40 gene has been associated with Alzheimer's disease. We have investigated the impact of this polymorphism on Parkinson's disease risk and age of onset, independently and in combination with apolipoprotein E alleles, in a group of 407 PD patients and 305 control subjects. No significant association was observed at the single allele, genotype, or haplotype levels. Our data suggest that the polymorphism is not a risk factor for Parkinson's disease in the Polish population.

Late onset Alzheimer's disease (LOAD) accounts for about 95% of all Alzheimer's disease cases. While the APOE e4 variant seems to have unparalleled influence on increased LOAD risk, it does not explain all of the heritability of LOAD. In this study, we present the application of a cost-effective, pooled DNA genome-wide association study (GWAS) to uncover genetic risk variants associated with LOAD in Polish women diagnosed with either mild cognitive impairment (MCI) or well-defined LOAD. A group of 141 patients (94 LOAD and 47 MCI), as well as 141 controls, were assayed using Affymetrix Genome-Wide Human SNP 6.0 arrays. Allele frequency distributions were compared using χ(2)-tests, and significantly associated SNPs at p < 0.0001 with a proxy SNP were selected. GWAS marker selection was conducted using PLINK, and selected SNPs were validated on DNA samples from the same cohort using KASPar Assays. In addition, to determine the genotype of APOE variants (rs429358, rs7412), a multiplex tetra-primer amplification refractory mutation system was applied. The GWAS revealed nine SNPs associated with MCI and/or LOAD. Of these, the association of seven SNPs was confirmed by genotyping of individual patients. Furthermore, the APOE e4 appeared to be a risk variant for LOAD, while the APOE e3 showed a protective effect. Multivariate analysis showed association between rs7856774 and LOAD, independently from the effect of APOE variation. Pooled DNA GWAS enabled the identification of a novel LOAD candidate risk variant, rs7856774 (9q21.33), tagging a possible genomic enhancer affecting proximal transcribed elements including DAPK1 gene.

APBB2 gene encodes for β-amyloid precursor protein-binding family B member 2, (APBB2, FE65-like, FE65L1), an adaptor protein binding to the cytoplasmatic domain of β-amyloid precursor protein (βAPP). Over-expression of APBB2 promotes formation of β-amyloid (Aβ), the main constituent of senile plaques. Polymorphisms within APBB2 gene have been proposed as candidate risk factors for Alzheimer's disease. However, their association with longevity has never been investigated. Here we present the first attempt to analyze APBB2 polymorphisms in centenarians. We used a PCR-RFLP method to analyze two intronic nucleotide substitutions: hCV1558625 (rs17443013) and rs13133980. We found no differences in genotype or allele distribution between centenarians and young controls. After stratification of centenarians upon their cognitive performance, the APBB2 rs13133980 G allele was over-represented in centenarians with severe cognitive impairment compared to individuals without this disability. Also the hCV1558625-rs13133980 AG haplotype increased relative risk for severe cognitive impairment in centenarians. Our results support the concept of APBB2 polymorphism association with cognitive performance in the oldest age.

In order to study oxidative stress in peripheral cells of Alzheimer's disease (AD) patients, immortalized lymphocytes derived from two peculiar cohorts of patients, referring to early onset AD (EOSAD) and subjects harboured AD related mutation (ADmut), were used. Oxidative stress was evaluated measuring i) the typical oxidative markers, such as HNE Michel adducts, 3 Nitro-Tyrosine residues and protein carbonyl on protein extracts, ii) and the antioxidant capacity, following the enzymatic kinetic of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRD). We found that the signs of oxidative stress, measured as oxidative marker levels, were evident only in ADmut but not in EOSAD patients. However, oxidative imbalance in EOSAD as well as ADmut lymphocytes was underlined by a reduced SOD activity and GRD activity in both pathological groups in comparison with cells derived from healthy subjects. Furthermore, a redox modulated p53 protein was found conformational altered in both EOSAD and ADmut B lymphocytes in comparison with control cells. This conformational altered p53 isoform, named "unfolded p53", was recognized by the use of two specific conformational anti-p53 antibodies. Immunoprecipitation experiments, performed with the monoclonal antibodies PAb1620 (that recognizes p53wt) and PAb240 (that is direct towards unfolded p53), and followed by the immunoblotting with anti-4-hydroxynonenal (HNE) and anti- 3-nitrotyrosine (3NT) antibodies, showed a preferential increase of nitrated tyrosine residues in unfolded p53 isoform comparing to p53 wt protein, in both ADmut and EOSAD. In addition, a correlation between unfolded p53 and SOD activity was further found. Thus this study suggests that ROS/RNS contributed to change of p53 tertiary structure and that unfolded p53 can be considered as an early marker of oxidative imbalance in these patients.

Mossbauer studies of Parkinsonian and control Substantia Nigra (SN) show that the overall amount of iron in SN is about the same in PD and control. At least 90% of this iron is ferritin-like and Fe2+ and/or neuromelanin iron, if present at all, can constitute only less than 10% of the overall iron. During storage in formalin, iron is slowly removed from ferritin and bound to a chelating agent.

Recently, it has been reported that TOMM40 variable-length poly-T sequence polymorphism (rs10524523) in combi- nation with APOE alleles (E2, E3, E4) significantly influences late-onset Alzheimer's disease (LOAD) age of onset. In a group of 414 LOAD patients, 173 centenarians and 305 neurologically healthy individuals, we investigated the impact of TOMM40 poly-T tracts on LOAD incidence, age of onset, and longevity. TOMM40 allelic variants were classified into four categories: short (S; 14-16T), long a( La; 20-22T), long b (Lb; 26-30T), and very long (VL; 31-39T). Our results demonstrate that La and Lb share similar characteristics in affecting LOAD risk, thus for some analyses they were combined into L category. We observed significantly lower frequency of VL allele (p < 0.0001) and significantly higher frequency of L alleles in the LOAD patients compared to the control individuals (p < 0.0001). S/S, S/VL, and VL/VL genotypes and VL-E2, S-E3, VL-E3 haplotypes are significantly associated with lower LOAD risk. VL-E3 haplotype carriers significantly more frequently developed LOAD when they were ≥79 years old. Additionally, S/L genotype is associated with a significantly increased LOAD risk (p < 0.0001). We conclude that in the carriers of TOMM40-APOE haplotypes comprising E4 allele, the TOMM40 rs10524523 allele does not play substantial role in establishing LOAD risk. Nevertheless, TOMM40 L allele increases the risk when E4 is absent. Finally, L allele, as well as genotypes (S/L, V/L) and haplotypes (L-E3, L-E4) comprising L significantly reduce the likelihood of living up to 100 years.

Background A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33. Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A, independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B. In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B, and CD33) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 dosage. Results We found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for EPHA1 (rs11767557; OR = 0.87, p = 5 × 10-4) and CD33 (rs3865444; OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two ARID5B variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the CD2AP variant (rs9349407, p = 0.56). Conclusions Our data overwhelmingly support the association of EPHA1 and CD33 variants with LOAD risk: addition of our data to the results previously reported (total n > 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10-15 (EPHA1) and 1.8 × 10-13 (CD33).

Background: The relationship between different paraoxonase (PON) gene polymorphisms and the risk of Alzheimer’s disease (AD) was studied several times and the results were controversial. Methods: We investigated the association of 4 single-nucleotide polymorphisms (SNPs) of the PON1 (M55L; Q192R; –161C/T) and the PON2 (C311S) genes that were shown to affect the risk of sporadic AD. We studied 360 Caucasian cases with late-onset AD and 354 nondemented controls. Results: No significant differences were observed between the studied PON SNPs and AD risk. The results did not change after stratification of the apolipoprotein E status. Meta-analyses of studies in Caucasians assessing the associations between the PON1 M55L, –161C/T and Q192R SNPs and the risk of AD were performed, and no associations were found. Conclusion: Our results suggest that the studied PON1 and PON2 polymorphisms are not associated with late-onset AD.

Background and purpose Inflammation plays a prominent role in Alzheimer disease (AD) pathogenesis. Interleukin-6 (IL-6), a pro-inflammatory cytokine, and some genetic variations in the IL-6 gene have been reported to be associated with a risk of AD. However, the results of the conducted studies are equivocal. Material and methods We genotyped IL-6 (–174 C/G) and apolipoprotein E gene (APOE) common polymorphisms in a large case-controlled study in a Polish population. We included 361 patients aged ≥ 65 years with AD (mean age 75.8 ± 5.3 years, 232 females [64.3%]) and 200 controls (75.3 ± 7.4 years; 119 females [59.5%]), without any neurological deficit, cognitive complaints or history of neurological diseases. The IL-6 polymorphism was genotyped using TaqMan SNP allelic discrimination by means of an ABI 7900HT (Applied Biosystems, Foster City, CA). Results The distribution of the IL-6 (–174 C/G) genotypes was similar to that in the controls (AD: C/C = 15.79%, C/G = 51.25%, G/G = 32.96% vs. controls: C/C = 21.50%, C/G = 45.50%, G/G = 33.0%, p > 0.05). Our study confirms previous reports that APOE 4 is strongly related to the risk of AD (OR = 6.17; 95% CI: 4.01–9.49). APOE status did not affect the distribution of the studied IL-6 polymorphism. Conclusion IL-6 (–174 C/G) polymorphism is not a risk factor for late onset AD in a Polish population.

We investigated the potential contribution of mitochondrial DNA (mtDNA) variants, haplogroups, and polymorphisms in nuclear genes essential for mitochondrial biogenesis and function (PGC-1α TFAM) to late-onset Alzheimer's disease (LOAD) risk. Epistatic interaction analysis was conducted between the studied variables. Our results demonstrate that mtDNA haplogroups and subhaplogroups with putative role in partial uncoupling of oxidative phosphorylation are significantly associated with a decreased LOAD risk (OR

A role for the immune system in the pathogenesis of Parkinson's Disease (PD) has previously been suggested. A recent genome-wide association (GWA) study identified an association between one single nucleotide polymorphism (SNP) in the human leucocyte antigen (HLA) region (HLA-DRA rs3129882) and PD in a population of American patients with European ancestry. In that study, the minor rs3129882 allele (G) was associated with an increased risk of PD under an additive model. Due to the increased likelihood of obtaining false positive results in GWA studies compared to studies conducted based on a hypothesis-driven approach, repeated validation of findings from GWA studies are necessary. Herein, we evaluated the association between rs3129882 and PD in three different Caucasian patient-control series (combined 1313 patients and 1305 controls) from the US, Ireland, and Poland. We observed no association (OR: 0.96, P = 0.50) between rs3129882 and PD when analyzing our data under an additive or dominant model. In contrast, when examined under a recessive model, the GG genotype was observed to be protective in the Irish (OR: 0.55, P = 0.008), Polish (OR: 0.67, P = 0.040) and combined (OR: 0.75, P = 0.006) patient-control series. In view of these diverging results, the exact role of genetic variation at the HLA region and susceptibility to PD remains to be resolved.

Parkinson disease (PD) is the most common neurodegenerative movement disorder with age-related prevalence. Approximately 1% of the population is affected at 65 years, which increases to 4%–5% in 85-year-olds.1 To date, several loci containing pathogenic or risk variants have been identified; the most recent, PARK16 , was nominated through 2 genome-wide association studies (GWAS) using samples of Japanese and European ancestry.2,3 This new locus, located in 1q32, was originally identified in the Asian study with p values ranging from 10 −7 to 10 −12 . PARK16 did not reach significance level in the European GWAS or its replication ( p value >10 −4 ); however, combining samples from stage I and II indicated an association. The most significant SNP in the European study (rs823128) showed a 1% difference in minor allele frequency (MAF) between patients with PD (4%) and control subjects (3%), resulting in an odds ratio (OR) of 0.66 ( p value = 7.3 × 10 −8 ) (of note, the allele frequencies seem to have been mistakenly switched in the combined analysis).3 In contrast, the MAF of rs823128 appears to be more common in the Japanese population, with a lower frequency in patients with PD (10%) …

Several neurodegenerative diseases, including Alzheimer's disease (AD), have etiology connected to abnormal protein self association. Copper-induced striking differences in amyloid-β40 aggregation, distinct from spontaneous self association, prompted us to study whether amyloid-β40 aggregation could be applied to differentiate between platelet poor plasma ultrafiltrates obtained from AD and control samples. We report, based on 20 AD and 18 age-matched controls, a significant difference in the concentration of short fibers induced by ultrafiltrated plasma from AD compared to control samples. The observed effect was independent of copper and other EDTA chelatable ions.