Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Recent advances in fungal serine protease inhibitors.

Four types of antifungal drugs are available that include inhibitors of ergosterol synthesis, of fungal RNA biosynthesis, and of cell wall biosynthesis as well as physiochemical regulators of fungal membrane sterols. Increasing resistance to antifungal drugs can severely limit treatment options of fungal nail infections, vaginal candidiasis, ringworm, blastomycosis, histoplasmosis, and Candida infections of the mouth, throat, and esophagus, among other infections. Development of strategies focused on new fungicides can effectively help tackle troublesome fungal diseases. The virulence and optimal growth of fungi depend on various extracellular secreted factors, among which proteases, such as serine proteases, are of particular interest. A specific extracellular proteolytic system enables fungi to survive and penetrate the tissues. Given the role of fungal proteases in infection, any molecule capable of selectively and specifically inhibiting their activity can lead to the development of potential drugs. Owing to their specific mode of action, fungal protease inhibitors can avoid fungal resistance observed with currently available treatments. Although fungal secreted proteases have been extensively studied as potential virulence factors, our understanding of the substrate specificity of such proteases remains poor. In this review, we summarize the recent advances in the design and development of specific serine protease inhibitors and provide a brief history of the compounds that inhibit fungal serine protease activity.

Oral complaints in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Acute myeloid leukemia belongs to proliferative diseases of the hematopoietic system. It is currently the leading indication for allogeneic hematopoietic stem cell transplantation. This study was designed to determine the most common subjective oral mucosa complaints in patients with acute myeloid leukemia after allogeneic hematopoietic cell transplantation, in relation to the type of conditioning used. MATERIAL AND METHODS: Eighty patients diagnosed with acute myeloid leukemia were assigned to two groups depending on the intensity of the conditioning regimen before transplantation: myeloablative and reduced-intensity chemotherapy. The oral symptoms were evaluated based on an authorial questionnaire designed for this analysis. The following oral mucosa subjective complaints were included: pain, paraesthesia, burning mouth sensation, taste disorders, excessive salivation, halitosis, and dryness of the oral mucosa. RESULTS: The most commonly reported subjective oral complaint in the examined patients was xerostomia, which was found in 92% of patients during the second visit, followed by spontaneous pain in the mouth (55%), burning (36%), and dysgeusia (20%). It occurred significantly more frequently in patients who underwent myeloablative conditioning. Moreover, it was observed that the frequency of complaints increased considerably after the transplantation, reaching a peak intensity during the second week following the procedure. CONCLUSIONS: Oral complaints significantly decrease the patients' quality of life during the transplantation and may lead to premature termination of the treatment. As the number of transplantations in patients with acute myeloid leukemia increases, further investigations of oral complaints and symptoms induced by the disease itself and by the therapeutic approaches are required.

Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study.

OBJECTIVE: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. METHODS: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. RESULTS: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. CONCLUSION: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

The Effect of Repetitive Transcranial Magnetic Stimulation on Motor Symptoms in Hereditary Spastic Paraplegia.

Background: Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited disorders affecting predominantly the motor cortex and pyramidal tract, which results in slowly progressing gait disorders, as well as spasticity and weakness of lower extremities. Repetitive transcranial magnetic stimulation (rTMS) has been previously investigated as a therapeutic tool for similar motor deficits in a number of neurologic conditions. The aim of this randomized, controlled trial was to investigate the therapeutic potential of rTMS in various forms of HSP, including pure and complicated forms, as well as adrenomyeloneuropathy. Methods: We recruited 15 patients (five women and 10 men; mean age 43.7 ± 10.6 years) with the mentioned forms of HSP. The intervention included five sessions of bilateral 10 Hz rTMS over primary motor areas of the muscles of lower extremities and five sessions of similar sham stimulation. Results: One patient dropped out due to seizure, and 14 patients completed the study protocol. After real stimulation, the strength of the proximal and distal muscles of lower extremities increased, and the spasticity of the proximal muscles decreased. Change in spasticity was still present during follow-up assessment. No effect was observed regarding gait velocity. No changes were seen after sham stimulation. A post hoc analysis revealed an inverse relation between motor threshold and the change of the strength after active rTMS. Conclusions: rTMS may have potential in improving weakness and spasticity of lower extremities in HSP, especially of proximal muscles whose motor areas are located more superficially. This trial is registered with Clinicaltrials.gov NCT03627416.

Subsyndromal delirium is associated with poor functional outcome after ischaemic stroke.

BACKGROUND AND PURPOSE: Subsyndromal delirium (SSD) refers to patients with delirious symptoms who do not meet the criteria for delirium. The aim was to determine the prognostic significance of SSD in stroke patients. METHODS: In all, 564 patients with ischaemic stroke (median age 71 years, 50.5% female) were included. The Confusion Assessment Method was used to assess symptoms of delirium and the Diagnostic and Statistical Manual of Mental Disorders, 5th edn, criteria were used to diagnose delirium. SSD was defined as one or more core features of delirium without fulfilling diagnostic criteria. Functional outcome was assessed using the modified Rankin Scale at 3 and 12 months after stroke. RESULTS: Delirium was diagnosed in 23.4% of patients and SSD in 10.3% of patients. SSD was associated with increased risk of poor functional outcome. The adjusted odds ratios (ORs) for unfavourable outcome at 3 and 12 months were 2.88 [95% confidence interval (CI) 1.43-5.79, P < 0.01] and 2.93 (95% CI 1.39-6.22, P < 0.01), respectively. In multivariate analysis, delirium was an independent predictor of poor functional outcome at 3 months (OR 6.41, 95% CI 3.36-12.21, P < 0.01) and 12 months (OR 6.11, 95% CI 3.05-12.27, P < 0.01) after stroke. Delirium was also independently associated with increased risk of death within 3 months (hazard ratio 3.68, 95% CI 1.69-8.02, P < 0.01) and 12 months (hazard ratio 3.76, 95% CI 2.05-6.90, P < 0.01). SSD was not associated with increased risk of death. CONCLUSIONS: In SSD patients the risk of poor functional outcome after stroke is increased and intermediate between patients with and patients without delirium.

Brain inflammasomes in stroke and depressive disorders: Regulation by oestrogen.

Neuroinflammation is a devastating pathophysiological process that results in brain damage and neuronal death. Pathogens, cell fragments and cellular dysfunction trigger inflammatory responses. Irrespective of the cause, inflammasomes are key intracellular multiprotein signalling platforms that sense neuropathological conditions. The activation of inflammasomes leads to the auto-proteolytic cleavage of caspase-1, resulting in the proteolysis of the pro-inflammatory cytokines interleukin (IL)1ß and IL18 into their bioactive forms. It also initiates pyroptosis, a type of cell death. The two cytokines contribute to the pathogenesis in acute and chronic brain diseases and also play a central role in human aging and psychiatric disorders. Sex steroids, in particular oestrogens, are well-described neuroprotective agents in the central nervous system. Oestrogens improve the functional outcome after ischaemia and traumatic brain injury, reduce neuronal death in Parkinson's and Alzheimer's disease, as well as in amyotrophic lateral sclerosis, attenuate glutamate excitotoxicity and the formation of radical oxygen species, and lessen the spread of oedema after damage. Moreover, oestrogens alleviate menopause-related depressive symptoms and have a positive influence on depressive disorders probably by influencing growth factor production and serotonergic brain circuits. Recent evidence also suggests that inflammasome signalling affects anxiety- and depressive-like behaviour and that oestrogen ameliorates depression-like behaviour through the suppression of inflammasomes. In the present review, we highlight the most recent findings demonstrating that oestrogens selectively suppress the activation of the neuroinflammatory cascade in the brain in acute and chronic brain disease models. Furthermore, we aim to describe putative regulatory signalling pathways involved in the control of inflammasomes. Finally, we consider that psychiatric disorders such as depression also contain an inflammatory component that could be modulated by oestrogen.

Thrombolysis and thrombectomy in patients treated with dabigatran with acute ischemic stroke: Expert opinion.

Systemic thrombolysis with rt-PA is contraindicated in patients with acute ischemic stroke anticoagulated with dabigatran. This expert opinion provides guidance on the use of the specific reversal agent idarucizumab followed by rt-PA and/or thrombectomy in patients with ischemic stroke pre-treated with dabigatran. The use of idarucizumab followed by rt-PA is covered by the label of both drugs.

Polymorphism in the chemokine receptor 7 gene (CCR7) is associated with previous myocardial infarction in patients undergoing elective coronary angiography.

Coronary artery disease (CAD) remains a major cause of death in developed countries. Both environmental and, less known, genetic factors contribute to progression of CAD to myocardial infarction (MI). Immune system is activated in patients with CAD through dendritic cells (DCs), which present plaque antigens to T lymphocytes. Production of proinflammatory cytokines by activated T cells contributes to plaque rupture in MI. Chemokine receptor 7 (CCR7) on DCs is required for their chemotaxis from plaque to lymph nodes. This makes possible an interaction of DCs with T lymphocytes and initiation of specific immune response. We hypothesized that single nucleotide polymorphisms (SNPs) in CCR7 gene locus are associated with previous MI in patients with CAD. To test this hypothesis, we genotyped six SNPs from the CCR7 gene locus in 300 consecutive patients, admitted for elective coronary angiography. We performed univariate-, multivariate- (including potential confounders) and haplotype-based tests of association of SNPs with previous MI and results of angiography. Allele A of rs17708087 SNP was associated with previous MI. This association remained significant after adjustment for age, sex, smoking, hypercholesterolaemia and drugs used by patients (odds ratio 2.13, 95% confidence interval: 1.13-3.86). Therefore, we conclude that CCR7 gene locus harbours a polymorphism that modifies risk of MI in patients with CAD. Replication of this association could be sought in a prospective cohort of initially healthy individuals.

The sphingosine 1-phosphate receptor agonist FTY720 is neuroprotective after cuprizone-induced CNS demyelination.

BACKGROUND AND PURPOSE: Modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes within the lymph nodes. Here, we evaluated the potential of an agonist at this receptor, FTY720 (fingolimod), to activate the promyelinating pathways within the brain to encourage remyelination and neuroprotection. EXPERIMENTAL APPROACH: In this study, we used the cuprizone model in male C57BL/6 mice and tested the promyelinating and neuroprotective effects of FTY720 after acute and chronic toxin-induced experimental demyelination. We used histological, immunohistochemical and gene expression methods. KEY RESULTS: The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone-induced demyelination. Robust endogenous remyelination was evident after acute, but impaired after chronic, demyelination. FTY720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Markers of gliosis (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein-positive spheroids in axons was less distinct in FTY720-treated animals, indicating that this compound alleviated ongoing axonal damage. CONCLUSIONS AND IMPLICATIONS: We show that even during endogenous remyelination, axonal degeneration continued at a low level, accumulating over time. This continuous neurodegenerative process was ameliorated by FTY720 treatment. FTY720 preserved CNS integrity by direct interaction with brain resident cells, the actions of which are still to be defined.

Clinical presentation of early-onset Alzheimer's disease as a result of mutation in exon 12 of the PSEN-1 gene.

INTRODUCTION: Mutations in the gene for presenilin 1 (PSEN-1) cause familial, early-onset Alzheimer's disease (EOAD). Diagnosis of EOAD is often a challenge because of the high frequency of atypical presentations. Clinical manifestation of EOAD may vary depending on underlying mutation; specific genetic mutations influence development of specific clinical phenotypes; however, intrafamilial phenotypic heterogeneity has also been noted in some pedigrees. CASE PRESENTATION: We report a case of a 36-year-old woman presenting with progressive behavioral disturbances, dementia, involuntary movements, pyramidal signs, epilepsy, and a family history of early-onset dementia accompanied by involuntary movements. On genetic testing, the mutation at codon 424 (Leu→Arg) in PSEN-1 gene was identified. CONCLUSION: Our case describes a new phenotype of a known mutation of PSEN-1 at codon 424.

Use of dairies by postreproductive flocks of European starlings.

Knowledge of the behavior and movement patterns of European starlings (Sturnus vulgaris L.) is important to wildlife managers that seek to resolve conflicts at livestock facilities. We captured and radio tagged 10 starlings at each of 5 dairies in northeastern Ohio. From September 19 to October 31, 2007, we obtained sufficient data from 40 birds to study their behavior and movements. The birds visited the dairies where they were initially captured (home sites) on 85% of the days, spending 58% of each day at the dairies. Onsite arrival and departure times were 2.5h after sunrise and 3.1h before sunset. Daily visits by radio-tagged cohorts from the other dairies were greatest for the 2 most proximate dairies (1.3 km apart), with number of visits between this pairing >7× that of the 9 other pairings combined (4.1-6.5 km apart). Two birds used their home sites intermittently as roosts, arriving 3.8h before sunset and departing 0.2h after sunrise. In addition to using home-site roosts, these birds also used a distant roost (22km) that was used by 36 of the 40 birds. The efficacy of starling management programs, especially lethal management, depends on degree of site fidelity, use of other facilities, and roosting behavior. For example, starlings that use dairies as roosting sites may require a different management strategy than required at dairies used as daytime sites because of differences in arrival and departure behavior. Our research will help resource managers evaluate current management strategies already in place and change them, if needed, to fit the behavior profile of starlings using dairies and other types of livestock facilities.

Regional heterogeneity of cuprizone-induced demyelination: topographical aspects of the midline of the corpus callosum.

The cuprizone model is a suitable animal model of de- and remyelination secondary to toxin-induced oligodendrogliopathy. From a pharmaceutical point of view, the cuprizone model is a valuable tool to study the potency of compounds which interfere with toxin-induced oligodendrocyte cell death or boost/inhibit remyelinating pathways and processes. The aim of this study was to analyze the vulnerability of neighboring white mater tracts (i.e., the fornix and cingulum) next to the midline of the corpus callosum which is the region of interest of most studies using this model. Male mice were fed cuprizone for various time periods. Different white matter areas were analyzed for myelin (anti-PLP), microglia (anti-IBA1), and astrocyte (anti-GFAP) responses by means of immunohistochemistry. Furthermore, Luxol fast blue-periodic acid Schiff stains were performed to validate loss of myelin-reactive fibers in the different regions. Cuprizone induced profound demyelination of the midline of the corpus callosum and medial parts of the cingulum that was paralleled by a significant astrocyte and microglia response. In contrast, lateral parts of the corpus callosum and the cingulum, as well as the fornix region which is just beneath the midline of the corpus callosum appeared to be resistant to cuprizone exposure. Furthermore, resistant areas displayed reduced astrogliosis and microgliosis. This study clearly demonstrates that neighboring white matter tracts display distinct vulnerability to toxin-induced demyelination. This important finding has direct relevance for evaluation strategies in this frequently used animal model for multiple sclerosis.

Electrophysiological correlates of attentional processes in patients with liver cirrhosis without minimal or clinically-overt hepatic encephalopathy.

Liver cirrhosis is often accompanied by a spectrum of cognitive deficits, labelled hepatic encephalopathy (HE). The precise specification of cognitive impairment associated with HE has not been yet elucidated. The aim of this study was an attempt to examine cortical function in cirrhotic patients using EEG event-related potentials during a demanding task involving selective attention. We compared group of 30 patients with liver cirrhosis without minimal or overt HE with education-, age- and sex-matched 29 non-cirrhotic controls. Both groups performed an attentional blink (AB) task, which requires detecting and identifying two target characters in a longer series of rapidly and sequentially presented characters. EEG signals from 32 electrodes were measured and then analyzed in the paradigm of event-related potentials (ERP). Though the groups did not differ in the detection rate of the target stimuli, ERP waveforms revealed two group differences of component amplitudes. The first difference was related to the waveform amplitude within the 200-400 ms after first target in the right frontal region (frontocentral N2 component). Moreover, in patient group this amplitude positively correlated with the blood plasma level of alkaline phosphatase and gamma-glutamyl transpeptidase. The second amplitude difference was observed in the midline parieto-occipital regions within the 400-600 ms after the first target (P3b component). The AB task and ERP analysis allowed to find differences in cortical functioning in cirrhotic patients even without overt cognitive deficits. Our finding demonstrates that liver dysfunction can influence cortical processing associated with detecting and categorizing stimulus change.

Cognitive evoked response potentials in patients with liver cirrhosis without diagnosis of minimal or overt hepatic encephalopathy. A pilot study.

Liver cirrhosis is often accompanied by cognitive deficits called minimal hepatic encephalopathy (MHE) when it is observed to a moderate extent. In the present study, brain activity and cognitive functioning were examined in patients with liver cirrhosis without MHE or overt clinical hepatic encephalopathy. A battery of neuropsychological tests and event related potentials (ERPs) were used. Moreover, an additional n-back task was administered with two difficulty levels (1- and 2-back). This task was designed to engage cognitive processes of storage and manipulation of information in working memory. The participants have to decide whether the letter shown was the same as a target (congruence condition). No significant differences were found in the performance of either the neuropsychological tests or the n-back task. However, the expected effects of decreased performance as well as a decrease in P3 amplitude with difficulty level were identified. The interaction of group x congruence condition was also observed in the P2 component time window. These results may indicate group differences manifesting in early stages of information processing in working memory. It confirms that the patients whose neuropsychological performance is within the normal range can still reveal subtle changes in CNS functioning visible in ERP research. The study confirms the usability of the ERP method in diagnosis of neurocognitive functions in patients with liver cirrhosis, which seems to be more sensitive than neuropsychological tests.

Genetic variation at CR1 increases risk of cerebral amyloid angiopathy.

OBJECTIVE: Accumulated evidence suggests that a variant within the CR1 gene (single nucleotide polymorphism rs6656401), known to increase risk for Alzheimer disease (AD), influences ß-amyloid (Aß) deposition in brain tissue. Given the biologic overlap between AD and cerebral amyloid angiopathy (CAA), a leading cause of intracerebral hemorrhage (ICH) in elderly individuals, we investigated whether rs6656401 increases the risk of CAA-related ICH and influences vascular Aß deposition. METHODS: We performed a case-control genetic association study of 89 individuals with CAA-related ICH and 280 individuals with ICH unrelated to CAA and compared them with 324 ICH-free control subjects. We also investigated the effect of rs6656401 on risk of recurrent CAA-ICH in a prospective longitudinal cohort of ICH survivors. Finally, association with severity of histopathologic CAA was investigated in 544 autopsy specimens from 2 longitudinal studies of aging. RESULTS: rs6656401 was associated with CAA-ICH (odds ratio [OR] = 1.61, 95% confidence interval [CI] 1.19-2.17, p = 8.0 × 10(-4)) as well as with risk of recurrent CAA-ICH (hazard ratio = 1.35, 95% CI 1.04-1.76, p = 0.024). Genotype at rs6656401 was also associated with severity of CAA pathology at autopsy (OR = 1.34, 95% CI 1.05-1.71, p = 0.009). Adjustment for parenchymal amyloid burden did not cancel this effect, suggesting that, despite the correlation between parenchymal and vascular amyloid pathology, CR1 acts independently on both processes, thus increasing risk of both AD and CAA. CONCLUSION: The CR1 variant rs6656401 influences risk and recurrence of CAA-ICH, as well as the severity of vascular amyloid deposition.

Interleukin 6-174G>C polymorphism and risk of aneurysmal subarachnoid hemorrhage: case-control study and meta-analysis.

OBJECTIVES: Vascular inflammation contributes to the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH). Interleukin 6 (IL6) is a proinflammatory cytokine involved in many vascular pathologies. Two studies analyzing an association of the functional IL6 gene -174G>C promoter polymorphism with aSAH provided inconsistent results. The aim of this study was to investigate whether this IL6 polymorphism is associated with aSAH in a Polish population. MATERIAL AND METHODS: We genotyped 276 aSAH patients and 581 unrelated control subjects. All were of Caucasian origin. In addition, a meta-analysis combining results of the current and previously published studies was conducted. RESULTS: The distribution of IL6 genotypes and alleles did not differ significantly between aSAH (GG - 29.7%, GC - 50.0%, CC - 20.2%, G - 54.7%) and control subjects (GG - 32.0%, GC - 47.3%, CC - 20.7%, G - 44.3%). In the meta-analysis, the IL6-174G>C polymorphism was not associated with aSAH risk either. CONCLUSIONS: We failed to find an association between the IL6 -174G>C polymorphism and aSAH in analyzed European populations.

Paraoxonase 1 gene polymorphisms do not influence the response to treatment in Alzheimer's disease.

BACKGROUND: Acetylcholinesterase inhibitors (AChEIs) are the treatment of choice for patients with Alzheimer's disease (AD). However, their efficacy is moderate and differs from patient to patient. Recent studies suggest that the Q192R variant of the paraoxonase 1 gene (PON1) might affect individual susceptibility to these drugs. METHODS: We investigated the influence of 3 single nucleotide polymorphisms (SNPs) in PON1 (rs 662, rs 854560, rs 705381) and the APOE common polymorphism in 101 Polish patients with late-onset AD in response to treatment with AChEIs. RESULTS: No significant differences were observed between carriers and non-carriers of the PON1 SNPs or the APOE common polymorphism in terms of treatment response. These results did not change after stratification of APOE status. CONCLUSION: Our results suggest that both the investigated PON1 and APOE common SNPs do not influence treatment response to AChEIs in patients with AD.

Paraoxonase gene polymorphism and the risk for Alzheimer's disease in the polish population.

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.