Efficacy and Safety of Oral Factor XIa Inhibitors in Stroke Prevention: A Systematic Review and Meta-Analysis.

INTRODUCTION: Despite preventive measures, stroke rates remain high in the primary and secondary prevention settings. Factor XIa inhibition may offer a novel, safe and effective antithrombotic option for stroke prevention. METHODS: We conducted a systematic review and meta-analysis including all available randomized controlled clinical trials (RCTs) that investigated the efficacy and safety of factor XIa inhibitors versus controls in primary or secondary stroke prevention. The primary efficacy and safety outcomes of interest were symptomatic ischemic stroke (IS) and the composite of major bleeding and clinically relevant non-major bleeding. RESULTS: Four phase II dose-finding RCTs were included, comprising a total of 4732 patients treated with factor XIa inhibitors versus 1798 controls. Treatment with factor XIa inhibitors did not reduce the risk of IS compared to controls (RR: 0.89; 95% CI: 0.67-1.17). The composite of symptomatic IS and covert infarcts on brain MRI (RR: 1.01; 95% CI: 0.87-1.18), the composite of symptomatic IS and transient ischemic attack (TIA; RR: 0.78; 95% CI: 0.61-1.01), and the composite of major adverse cardiovascular events (RR: 1.07; 95% CI: 0.87-1.31) did not differ between the treatment groups. Treatment with factor XIa inhibitors did not increase the risk of the composite of major bleeding and clinically relevant non-major bleeding (RR: 1.19; 95% CI: 0.65-2.16), major bleeding alone (RR: 1.19; 95% CI: 0.64-2.22), intracranial bleeding (RR: 0.91; 95% CI: 0.26-3.19) or all-cause mortality (RR: 1.21; 95% CI: 0.77-1.90). CONCLUSION: This meta-analysis provides reassuring evidence regarding the safety of factor XIa inhibitors. These findings, coupled with potential signals of efficacy in reducing IS (and TIA), underscore the importance of ongoing phase III RCTs for providing definitive data regarding the effect of factor XIa inhibition on stroke prevention.

Pesticides and tremor: An overview of association, mechanisms and confounders.

Pesticides are a heterogeneous class of chemicals mainly used for the protection of crops from pests. Because of their very widespread use, acute or/and chronic exposure to these chemicals can lead to a plethora of sequelae inflicting diseases, many of which involve the nervous system. Tremor has been associated with pesticide exposure in human and animal studies. This review is aimed at assessing the studies currently available on the association between the various types of pesticides/insecticides and tremor, while also accounting for potential confounding factors. To our knowledge, this is the first coherent review on the subject. After appraising the available evidence, we call for more intensive research on this topic, as well as intonate the need of implementing future preventive measures to protect the exposed populations and to reduce potential disabilities and social drawbacks.

High Hereditary Transthyretin-Related Amyloidosis Prevalence in Crete: Genetic Heterogeneity and Distinct Phenotypes.

Background and Objectives: Our goal was to study hereditary transthyretin-related amyloidosis (hATTR) in Crete, Greece. Methods: We aimed at ascertaining all hATTR cases in Crete, an island of 0.62 million people. For this, we evaluated patients with polyneuropathy, autonomic involvement, cardiomyopathy, and/or ophthalmopathy suggestive of hATTR, who presented to the physicians of this study or were referred to them by other physicians. Genetic analyses were performed on all patients suspected of suffering from hATTR. We included in our observational longitudinal cohort study all individuals, residents of Crete, who, during the study period (1993-2019), were found to carry a pathogenic TTR variant. Results: Over the past 27 years, 30 individuals (15 female patients, 15 male patients), from 12 apparently unrelated families, were diagnosed with hATTR, whereas evaluation of their offspring identified 5 asymptomatic TTR pathogenic variant carriers. The most prevalent TTR variant detected was p.Val50Met, affecting 19 patients (11 female patients, 8 male patients) and causing a rather consistent phenotype characterized by predominant polyneuropathy of early adult onset (median age of symptom onset: 30 years; range: 18-37 years). Specifically, patients affected by the p.Val50Met TTR variant experienced progressive sensorimotor disturbances, involving mainly the lower extremities, associated with autonomic and/or gastrointestinal dysfunction. The second most frequent TTR variant was p.Val114Ala, found in 10 patients (4 female patients, 6 male patients) who were affected at an older age (median age of symptom onset: 70 years; range: 54-78 years). This variant caused a predominantly cardiomyopathic phenotype, manifested by congestive heart failure and associated with peripheral neuropathy, carpal tunnel syndrome, and/or autonomic involvement. In these patients, cardiac amyloid deposition was detected on 99m-technetium pyrophosphate scintigraphy and/or heart biopsy. The third TTR variant (p.Arg54Gly) was found in a 50-year-old male patient with ophthalmopathy due to vitreous opacities and positive family history for visual loss. As 22 patients were alive at the end of the study, we calculated the hATTR prevalence in Crete to be 35 cases per 1 million inhabitants. Discussion: Our study revealed that the prevalence of hATTR in Crete is one of the world's highest. Three different pathogenic TTR variants causing distinct clinical phenotypes were identified in this relatively small population pool.

Lack of an association between SCFD1 rs10139154 polymorphism and amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Through a genome­wide association study (GWAS), the Sec1 family domain­containing protein 1 (SCFD1) rs10139154 variant at 14q12 has emerged as a risk factor gene for ALS. Moreover, it has been reported to influence the age at onset (AAO) of patients with ALS. The aim of the present study was to assess the association of the SCFD1 rs10139154 polymorphism with the risk of developing ALS. For this purpose, 155 patients with sporadic ALS and 155 healthy controls were genotyped for the SCFD1 rs10139154. The effect of the SCFD1 rs10139154 polymorphism was then examined on the following parameters: i) The risk of developing ALS; ii) the AAO of ALS; iii) the site of ALS onset (patients with bulbar onset ALS vs. healthy controls; and patients with limb onset ALS vs. healthy controls); and iv) the AAO of ALS onset with subgroup analyses based on the site of onset (bulbar and limb, crude and adjusted for sex). The analysis of all the outcomes was performed assuming five genetic models. Crude and adjusted analyses were applied. The threshold for statistical significance was set at 0.05. The results revealed no association between SCFD1 rs10139154 and any of the examined phenotypes in any of the models examined. On the whole, based on the findings of the present study, SCFD1 rs10139154 does not appear to play a determining role in the risk of developing ALS.

The Prognostic Value of Quantitative EEG in Patients Undergoing Mechanical Thrombectomy for Acute Ischemic Stroke.

PURPOSE: Previous work has shown that quantitative EEG measures correlate with the severity of ischemic stroke. This has not been systematically validated in patients with acute ischemic stroke who have undergone mechanical thrombectomy. METHODS: Data were collected from 73 patients who underwent mechanical thrombectomy and had a standard head set EEG performed during their hospital admission. For each patient, the global delta-alpha ratio (DAR) and its difference between the two hemispheres were calculated. Associations between the global and interhemispheric DAR difference with the patients' National Institutes of Health Stroke and Modified Rankin Scale scores at discharge and 3 months after thrombectomy were assessed. RESULTS: The interhemispheric DAR difference correlated with the National Institutes of Health Stroke scores at discharge (Spearman R = 0.41, P = 0.0008), National Institutes of Health Stroke scores at 3 months (Spearman R = 0.60, P = 0.02) and Modified Rankin Scale scores at 3 months (Spearman R = 0.27, P = 0.01). In contrast, the global DAR did not correlate significantly with any of these clinical outcomes when evaluated as continuous variables. In a multivariate logistic regression model, both the interhemispheric DAR difference (ß = 0.25, P = 0.03) and the infarct volume (ß = 0.02, P = 0.03) were independently predictive of good versus poor functional outcome (Modified Rankin Scale score ≤2 vs. >2) at 3 months. CONCLUSIONS: The quantitative EEG measure of interhemispheric slow relative to fast frequencies power asymmetry correlated with the discharge and 3-month National Institutes of Health Stroke and Modified Rankin Scale scores and provided added value to infarct volume in predicting functional outcome at 3 months. These data support the prognostic value of quantitative EEG in ischemic stroke patients who have undergone mechanical thrombectomy.

Genetic cause of epilepsy in a Greek cohort of children and young adults with heterogeneous epilepsy syndromes.

We describe a cohort of 10 unrelated Greek patients (4 females, 6 males; median age 6.5 years, range 2-18 years) with heterogeneous epilepsy syndromes with a genetic basis. In these patients, causative genetic variants, including two novel ones, were identified in 9 known epilepsy-related genes through whole exome sequencing. A patient with glycine encephalopathy was a compound heterozygote for the p.Arg222Cys and the p.Ser77Leu AMT variant. A patient affected with Lafora disease carried the homozygous p.Arg171His EPM2A variant. A de novo heterozygous variant in the GABRG2 gene (p.Pro282Thr) was found in one patient and a pathogenic variant in the GRIN2B gene (p.Gly820Val) in another patient. Infantile-onset lactic acidosis with seizures was associated with the p.Arg446Ter PDHX gene variant in one patient. In two additional epilepsy patients, the p.Ala1662Val and the novel non-sense p.Phe1330Ter SCN1A gene variants were found. Finally, in 3 patients we observed a novel heterozygous missense variant in SCN2A (p.Ala1874Thr), a heterozygous splice site variant in SLC2A1 (c.517-2A>G), as a cause of Glut1 deficiency syndrome, and a pathogenic variant in STXBP1 (p.Arg292Leu), respectively. In half of our cases (patients with variants in the GRIN2B, SCN1A, SCN2A and SLC2A1 genes), a genetic cause with potential management implications was identified.

Acute reperfusion therapies for acute ischemic stroke patients with unknown time of symptom onset or in extended time windows: an individualized approach.

Recent randomized controlled clinical trials (RCTs) have revolutionized acute ischemic stroke care by extending the use of intravenous thrombolysis and endovascular reperfusion therapies in time windows that have been originally considered futile or even unsafe. Both systemic and endovascular reperfusion therapies have been shown to improve outcome in patients with wake-up strokes or symptom onset beyond 4.5 h for intravenous thrombolysis and beyond 6 h for endovascular treatment; however, they require advanced neuroimaging to select stroke patients safely. Experts have proposed simpler imaging algorithms but high-quality data on safety and efficacy are currently missing. RCTs used diverse imaging and clinical inclusion criteria for patient selection during the dawn of this novel stroke treatment paradigm. After taking into consideration the dismal prognosis of nonrecanalized ischemic stroke patients and the substantial clinical benefit of reperfusion therapies in selected late presenters, we propose rescue reperfusion therapies for acute ischemic stroke patients not fulfilling all clinical and imaging inclusion criteria as an option in a subgroup of patients with clinical and radiological profiles suggesting low risk for complications, notably hemorrhagic transformation as well as local or remote parenchymal hemorrhage. Incorporating new data to treatment algorithms may seem perplexing to stroke physicians, since treatment and imaging capabilities of each stroke center may dictate diverse treatment pathways. This narrative review will summarize current data that will assist clinicians in the selection of those late presenters that will most likely benefit from acute reperfusion therapies. Different treatment algorithms are provided according to available neuroimaging and endovascular treatment capabilities.

A Prospective, Observational, Cohort Study to Assess the Efficacy and Safety of Prolonged-Release Fampridine in Cognition, Fatigue, Depression, and Quality of Life in Multiple Sclerosis Patients: The FAMILY Study.

INTRODUCTION: The efficacy of prolonged-release fampridine (PR-FAM) may extend in multiple sclerosis (MS) beyond walking ability. The objective of this study was to evaluate the effect of PR-FAM treatment on cognition, fatigue, depression, and quality of life (QoL) in adult patients with MS in a real-world setting. METHODS: FAMILY was a multi-center, prospective, observational, real-world cohort study of MS patients receiving PR-FAM in the outpatient setting. Patients were treated as per PR-FAM's local prescribing information for 6 months. Standardized protocols and questionnaires were used to evaluate changes in cognition (PASAT; Paced Auditory Serial Addition Test), fatigue (MFIS; Modified Fatigue Impact Scale), depression (BDI-II; Beck Depression Inventory-II) and QoL (MusiQoL; MS International Quality-of-Life questionnaire, MSIS-29; Multiple Sclerosis Impact Scale: PHYS and PSYCH subscales) at 3 and 6 months compared to baseline. RESULTS: In total, 102 eligible patients from 8 sites in Greece were analysed, of whom 92 completed the study and 10 discontinued. At 6 months, PR-FAM treatment resulted in improvements from baseline in PASAT-3'' (p = 0.044), MFIS (p < 0.001), BDI-II (p < 0.001), MusiQoL (p < 0.001) and MSIS-29-PHYS (p = 0.012) and MSIS-PSYCH (p < 0.001). A positive effect was evident already at 3 months in PASAT-3'' (ns), MFIS (p = 0.020), BDI-II (p = 0.034), MusiQoL (p = 0.001), MSIS-29-PHYS (ns) and MSIS-29-PSYCH (p < 0.001). CONCLUSIONS: This observational study provides new data to the current literature in support of PR-FAM's positive effects in cognition, fatigue, depression, and QoL in a large, heterogeneous group of Greek MS patients in the real-world setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03164018.

Genetic cause of heterogeneous inherited myopathies in a cohort of Greek patients.

Inherited muscle disorders are caused by pathogenic changes in numerous genes. Herein, we aimed to investigate the etiology of muscle disease in 24 consecutive Greek patients with myopathy suspected to be genetic in origin, based on clinical presentation and laboratory and electrophysiological findings and absence of known acquired causes of myopathy. Of these, 16 patients (8 females, median 24 years-old, range 7 to 67 years-old) were diagnosed by Whole Exome Sequencing as suffering from a specific type of inherited muscle disorder. Specifically, we have identified causative variants in 6 limb-girdle muscular dystrophy genes (6 patients; ANO5, CAPN3, DYSF, ISPD, LAMA2, SGCA), 3 metabolic myopathy genes (4 patients; CPT2, ETFDH, GAA), 1 congenital myotonia gene (1 patient; CLCN1), 1 mitochondrial myopathy gene (1 patient; MT-TE) and 3 other myopathy-associated genes (4 patients; CAV3, LMNA, MYOT). In 6 additional family members affected by myopathy, we reached genetic diagnosis following identification of a causative variant in an index patient. In our patients, genetic diagnosis ended a lengthy diagnostic process and, in the case of Multiple acyl-CoA dehydrogenase deficiency and Pompe's disease, it enabled specific treatment to be initiated. These results further expand the genotypic and phenotypic spectrum of inherited myopathies.

The role of MiRNA-21 in gliomas: Hope for a novel therapeutic intervention?

Gliomas are the most common primary brain tumors in adults. They are generally very resistant to treatment and are therefore associated with negative outcomes. MicroRNAs (miRNAs) are small, non-coding RNA molecules that affect many cellular processes by regulating gene expression and, post-transcriptionally, the translation of mRNAs. MiRNA-21 has been consistently shown to be upregulated in glioma and research has shown that it is involved in a wide variety of biological pathways, promoting tumor cell survival and invasiveness. Furthermore, it has been implicated in resistance to treatment, both against chemotherapy and radiotherapy. In this review, we gathered the existent data on miRNA-21 and gliomas, in terms of its expression levels, association with grade and prognosis, the pathways it involves and its targets in glioma, and finally how it leads to treatment resistance. Furthermore, we discuss how this knowledge could be applied in clinical practice in the years to come. To our knowledge, this is the first review to assess in extent and depth the role of miRNA-21 in gliomas.

Unraveling the Possible Routes of SARS-COV-2 Invasion into the Central Nervous System.

PURPOSE OF REVIEW: To describe the possible neuroinvasion pathways of Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2), the virus responsible for the Coronavirus disease-19 (Covid-19) pandemic. RECENT FINDINGS: We present data regarding the family of Coronaviruses (CoVs) and the central nervous system (CNS), and describe parallels between SARS-CoV-2 and other members of the family, which have been investigated in more depth and combine these findings with the recent advancements regarding SARS-CoV-2. SUMMARY: SARS-CoV-2 like other CoVs is neuroinvasive, neurotropic and neurovirulent. Two main pathways of CNS penetration seem to be the strongest candidates, the hematogenous and the neuronal. Τhe olfactory route in particular appears to play a significant role in neuroinvasion of coronaviruses and SARS-CoV-2, as well. However, existing data suggest that other routes, involving the nasal epithelium in general, lymphatic tissue and the CSF may also play roles in SARS-CoV-2 invasion into the CNS.

Posterior Reversible Encephalopathy Syndrome, Multiple Sclerosis and interferon therapy: Association, co-incidence or convoluted interplay?

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) has only rarely been reported in patients with multiple sclerosis (MS). METHODS: Case report of a patient with relapsing remitting (RR) MS patient on interferon (INF) treatment, who developed posterior fossa PRES. RESULTS: A 46-year-old male diagnosed with RR MS in 2010 was placed on INF beta-1a therapy. He remained in clinical remission for seven years. He then presented with headache of one month duration and worsening upper extremity ataxia. Cranial MRI revealed two new enhancing cerebellar lesions (one with tumefactive features). Within the next 10 days the patient developed severe holocephalic headache, vomiting, altered consciousness and gait instability. Urgent brain MRI revealed diffuse hyperintense lesions in T2WI and FLAIR sequences in bilateral cerebellar hemispheres and the right thalamus, with marked swelling, increased diffusivity indicative of vasogenic edema and patchy-nodular enhancement, while smaller lesions were also found in posterior temporal, parietal and occipital lobes. Severely elevated blood pressure was noted. Treatment with hypertonic agents, esmolol drip and IV steroids was instituted, resulting in remarkable improvement within the next several days. Repeat MRI showed almost complete resolution of the cerebellar lesions. Interferon beta was discontinued and blood pressure remained well controlled. CONCLUSIONS: Patients with RR MS on IFN beta therapy can develop PRES via the combination of hypertension and endothelial dysfunction by IFN, even when stable on this treatment. Neurologists should be keen to differentiate the appearance of PRES lesions from those of fulminant MS relapse, opportunistic infections or malignancy.

Patent Foramen Ovale in Cryptogenic Ischemic Stroke: Direct Cause, Risk Factor, or Incidental Finding?

Patent foramen ovale (PFO) has been associated with cryptogenic stroke. There is conflicting data and it remains uncertain whether PFO is the direct cause, a risk factor or an incidental finding. Potential stroke mechanisms include paradoxical embolism from a venous clot which traverses the PFO, in situ clot formation within the PFO, and atrial arrhythmias due to electrical signaling disruption. Main risk factors linked with PFO-attributable strokes are young age, PFO size, right-to-left shunt degree, PFO morphology, presence of atrial septal aneurysm, intrinsic coagulation-anticoagulation systems imbalance, and co-existence of other atrial abnormalities, such as right atrial septal pouch, Eustachian valve and Chiari's network. These may act independently or synergistically, multiplying the risk of embolic events. The RoPE score, a scale that includes factors such as young age, cortical infarct location and absence of traditional stroke risk factors, is associated with the probability of a PFO being pathogenic and stroke recurrence risk after the index stroke. Multiple investigators have attempted to correlate other PFO features with the risk of PFO-related stroke, but further investigation is needed before any robust conclusions are reached. PFO presence in young patients with cryptogenic stroke should be considered as etiologically suspect. Caution should be exercised in interpreting the relevance of other PFO features.

Intravenous thrombolysis in patients with chronic kidney disease: A systematic review and meta-analysis.

OBJECTIVE: To determine the association of chronic kidney disease (CKD) with the safety and efficacy of IV thrombolysis (IVT) among patients with acute ischemic stroke (AIS). METHODS: A systematic review and pairwise meta-analysis of studies involving patients with CKD undergoing IVT for AIS were conducted to evaluate the following outcomes: symptomatic intracranial hemorrhage (sICH), asymptomatic and any intracranial hemorrhage (ICH), in-hospital and 3-month mortality, 3-month favorable functional outcome (FFO; modified Rankin Scale [mRS] score 0-1), and 3-month functional independence (FI, mRS score 0-2). CKD was defined with estimated glomerular filtration rate (eGFR) ranging from mild (eGFR 60-89 mL/min) to moderate (eGFR 30-59 mL/min) to severe (eGFR 15-29 mL/min). RESULTS: We identified 20 studies comprising 60,486 patients with AIS treated with IVT. In unadjusted analyses, CKD was associated with sICH according to the National Institute of Neurological Disorders and Stroke (NINDS) (7 studies; odds ratio [OR] 1.41, 95% confidence interval [CI] 1.19-1.67) and European Cooperative Acute Stroke Study (ECASS) II (9 studies; OR 1.37, 95% CI 1.01-1.85) definitions, any ICH (8 studies; OR 1.42, 95% CI 1.18-1.70), 3-month mortality (9 studies; OR 2.20, 95% CI 1.72-2.81), 3-month FFO (8 studies; OR 0.58, 95% CI 0.47-0.72), and 3-month FI (8 studies; OR 0.57, 95% CI 0.46-0.71). In adjusted analyses, CKD was associated with sICH according to NINDS (4 studies; ORadj 1.34, 95% CI 1.01-1.79) and ECASS II (3 studies; ORadj 2.08, 95% CI 1.27-3.43) definitions, any ICH (6 studies; ORadj 1.41, 95% CI 1.01-1.97), in-hospital mortality (2 studies; ORadj 1.19, 95% CI 1.09-1.30), and 3-month FFO (6 studies; ORadj 0.80, 95% CI 0.70-0.92). CONCLUSIONS: After adjustment for confounders in this pairwise meta-analysis, moderate to severe CKD is associated with increased risks of ICH and worse functional outcomes among patients with AIS treated with IVT.

Is There Any Clinical Value of Adding 123I-Metaiodobenzylguanidine Myocardial Scintigraphy to 123I-Ioflupane (DaTscan) in the Differential Diagnosis of Parkinsonism?

PURPOSE: The aim of the study is to evaluate the impact of myocardial I-metaiodobenzylguanidine (MIBG) in the diagnosis, clinical management, and differential diagnosis of Parkinson disease (PD) and non-PD parkinsonism. METHODS: The study enrolled 41 patients with parkinsonism. An initial diagnosis was reached after thorough clinical and imaging evaluation. After 2 to 5 years of follow-up, a final diagnosis was established. All patients underwent, soon after their initial visit, presynaptic striatal DaT scintigraphy with I-FP-CIT (DaTscan) and I-MIBG myocardial scintigraphy. DaTscan is not specific to distinguish among different types of neurodegenerative parkinsonism. I-MIBG myocardial scintigraphy displays the functional status of cardiac sympathetic nerves, which is reduced in PD/dementia with Lewy bodies (DLB) and normal in atypical parkinsonian syndromes and secondary or nondegenerative parkinsonism. RESULTS: No patients showed adverse effects during or after both scintigraphies. A positive DaTscan was found in all patients in the PD/DLB group (17/17) and in 15 of 24 patients in the non-PD group. Myocardial I-MIBG scintigraphy was associated with lower sensitivity (82% vs 100%) but higher specificity than DaTscan (79% vs 38%) in diagnosis PD/DLB from non-PD parkinsonism. A positive scan result on both techniques, to confirm diagnosis of PD/DLB, significantly improved the specificity of DaTscan, from 38% to 75%, with no reduction in sensitivity. CONCLUSIONS: Myocardial I-MIBG imaging provides complementary value to I-FP-CIT in the proper diagnosis, treatment plan, and differential diagnosis between PD and other forms of parkinsonism.

CYP1A2 rs762551 and ADORA2A rs5760423 Polymorphisms in Patients with Blepharospasm.

Blepharospasm (BSP) is a neurological movement disorder. Coffee consumption has been found to have a protective effect against BSP. BSP and apraxia of eyelid opening are particularly common among patients with PD. The CYP1A2 rs762551 and ADORA2A rs5760423 variants have been previously marginally associated with the risk of PD and are also implicated in caffeine metabolism pathways. The aim of the present study was to evaluate the effect of the CYP1A2 rs762551 and ADORA2A rs5760423 variants on BSP. A Southeastern European Caucasian (SEC) cohort of 206 BSP patients and 206 healthy controls was genotyped for rs762551 and rs5760423. CYP1A2 rs762551 was associated with a decreased BSP risk in the dominant (OR (95% CI) 0.62 (0.41-0.92), p = 0.017), log-additive (OR (95% CI) 0.68 (0.51-0.92), p = 0.011), and co-dominant modes (for the CC genotype OR (95% CI) 0.49 (0.25-0.93), p = 0.038). We provide preliminary evidence that CYP1A2 rs762551 is associated with BSP. Further studies and replication of our results are needed.

Does the CD33 rs3865444 Polymorphism Confer Susceptibility to Alzheimer's Disease?

Alzheimer's disease (AD) is a complex genetic disorder. To date, published data have reported conflicting results on the role of CD33 rs3865444 polymorphism in AD. The present study aimed at evaluating the effect of rs3865444 on AD in a large cohort of Greek native patients with AD. We also conducted a meta-analysis by pooling information from different studies on the same topic. Patients with AD (n = 327) and healthy controls (n = 327) were analyzed and genotyped for rs3865444. Single locus analyses were run to explore possible associations between CD33 rs3865444 polymorphism and AD. Our analysis yielded no significant interaction between AD and the CD33 rs3865444 polymorphism. The lack of interaction between the two variables persisted even after a pooled meta-analysis of 8 studies (with 13 datasets), with 4015 AD cases and 7981 controls. The overall results do not support the hypothesis that CD33 rs3865444 polymorphism increases the risk of AD. The results also suggest that the identification of functional variants in CD33 that are indisputably correlated with AD may be an important factor to investigate in future genetic screening studies.