Type 2 Diabetes Mellitus as a Risk Factor for Alzheimer's Disease: Review and Meta-Analysis.

Alzheimer's disease is the most common type of dementia, reaching 60-80% of case totals, and is one of the major global causes of the elderly population's decline in functionality concerning daily life activities. Epidemiological research has already indicated that, in addition to several others metabolic factors, diabetes mellitus type 2 is a risk factor of Alzheimer's disease. Many molecular pathways have been described, and at the same time, there are clues that suggest the connection between type 2 diabetes mellitus and Alzheimer's disease, through specific genes, autophagy, and even inflammatory pathways. A systematic review with meta-analysis was conducted, and its main goal was to reveal the multilevel connection between these diseases.

Neurological manifestations of long-COVID syndrome: a narrative review.

Accumulating evidence points toward a very high prevalence of prolonged neurological symptoms among coronavirus disease 2019 (COVID-19) survivors. To date, there are no solidified criteria for 'long-COVID' diagnosis. Nevertheless, 'long-COVID' is conceptualized as a multi-organ disorder with a wide spectrum of clinical manifestations that may be indicative of underlying pulmonary, cardiovascular, endocrine, hematologic, renal, gastrointestinal, dermatologic, immunological, psychiatric, or neurological disease. Involvement of the central or peripheral nervous system is noted in more than one-third of patients with antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data. The most frequent neurological manifestations of 'long-COVID' encompass fatigue; 'brain fog'; headache; cognitive impairment; sleep, mood, smell, or taste disorders; myalgias; sensorimotor deficits; and dysautonomia. Although very limited evidence exists to date on the pathophysiological mechanisms implicated in the manifestation of 'long-COVID', neuroinflammatory and oxidative stress processes are thought to prevail in propagating neurological 'long-COVID' sequelae. In this narrative review, we sought to present a comprehensive overview of our current understanding of clinical features, risk factors, and pathophysiological processes of neurological 'long-COVID' sequelae. Moreover, we propose diagnostic and therapeutic algorithms that may aid in the prompt recognition and management of underlying causes of neurological symptoms that persist beyond the resolution of acute COVID-19. Furthermore, as causal treatments for 'long-COVID' are currently unavailable, we propose therapeutic approaches for symptom-oriented management of neurological 'long-COVID' symptoms. In addition, we emphasize that collaborative research initiatives are urgently needed to expedite the development of preventive and therapeutic strategies for neurological 'long-COVID' sequelae.

Guillain-Barré syndrome and fulminant encephalomyelitis following Ad26.COV2.S vaccination: double jeopardy.

This correspondence comments on a published article presenting a case of rhombencephalitis following SARS-CoV-2-vaccination with the mRNA vaccine BNT162b2 (Pfizer/BioNTech). We also present the case of a 47-year-old man who developed Guillain-Barré-syndrome and a fulminant encephalomyelitis 28 days after immunization with Ad26.COV2.S (Janssen/Johnson & Johnson). Based on the presented cases, we underscore the importance of clinical awareness for early recognition of overlapping neuroimmunological syndromes following vaccination against SARS-CoV-2. Additionally, we propose that that role of autoantibodies against angiotensin-converting enzyme 2 (ACE2) and the cell-surface receptor neuropilin-1, which mediate neurological manifestations of SARS-CoV-2, merit further investigation in patients presenting with neurological disorders following vaccination against SARS-CoV-2.

Omentin Is Independently Associated with Stroke Severity and Ipsilateral Carotid Artery Stenosis in Patients with Acute Cerebral Ischemia.

Mounting evidence indicates an association between adipokines and inflammation-related atherosclerosis. Here, we sought to investigate the association of vaspin and omentin with clinical characteristics and outcomes of patients with acute cerebral ischemia (ACI). Consecutive ACI patients were evaluated within 24 h from symptom-onset. Stroke aetiology was classified using TOAST criteria. Adipokines were assayed using quantikine enzyme immunoassay commercially available kits. Stroke severity was assessed by NIHSS-score, and ipsilateral carotid stenosis (≥50% by NASCET criteria) by ultrasound and CT/MR angiography. Major cerebrovascular events were assessed at three months. We included 135 ACI patients (05 (78%) and 30 (22%) with acute ischemic stroke and transient ischemic attack, respectively; mean age ± SD: 59 ± 10 years; 68% men; median NIHSS-score: 3 (IQR:1-7)). Omentin was strongly correlated to admission stroke severity (Spearman rho coefficient: +0.303; p < 0.001). Patients with ipsilateral carotid stenosis had higher omentin levels compared to patients without stenosis (13.3 ± 8.9 ng/mL vs. 9.5 ± 5.5 ng/mL, p = 0.014). Increasing omentin levels were independently associated with higher stroke severity (linear regression coefficient = 0.290; 95%CI: 0.063-0.516; p = 0.002) and ipsilateral carotid stenosis (linear regression coefficient = 3.411; 95%CI: 0.194-6.628; p = 0.038). No association of vaspin with clinical characteristics and outcomes was found. Circulating omentin may represent a biomarker for the presence of atherosclerotic plaque, associated with higher stroke severity in ACI patients.

Referral for "Neoadjuvant Chemotherapy" for Muscle-Invasive Bladder Cancer to a Multidisciplinary Board: Patterns, Management and Outcomes.

BACKGROUND: Utilization of neoadjuvant chemotherapy for the treatment of muscle invasive bladder cancer in everyday practice differs from that of clinical trials. We describe the patterns of referral for "neoadjuvant chemotherapy", treatment and outcomes in a multidisciplinary tumor board. METHODS: This was an observational study. Patients referred for neoadjuvant chemotherapy received 4 cycles of dose-dense gemcitabine/cisplatin and were then assessed for definitive local therapy. Patients had a minimum follow-up of 2 years. Primary objective was a 3-year disease-free survival rate. RESULTS: Forty-six patients (clinical stages II: 28, IIIA: 9, IIIB: 4, IVA: 3, missing: 2) were included. Following chemotherapy, 30 underwent radical cystectomy, 8 radiotherapy and 8 no further therapy. Pathological downstaging was observed in 14 (46.6%) of the 30 patients who underwent radical cystectomy; clinical TNM staging was correlated with disease-free survival in the whole population, while clinical and pathological stages, as well as pathological downstaging, were correlated with disease-free survival in patients undergoing radical cystectomy. Three-year disease-free survival rates for the whole cohort and for patients undergoing radical cystectomy were 67.3% (95% confidence interval [CI]: 51-79.2) and 65.2 (95% CI: 44.9-79.6), respectively. CONCLUSION: Real-world muscle invasive bladder cancer patients who receive neoadjuvant chemotherapy are characterized by more advanced diseases and less frequent radical surgery than those included in clinical trials. Nevertheless, outcomes were comparable and, therefore, offering patients with stage II-IVA muscle invasive bladder cancer neoadjuvant chemotherapy after assessment by multidisciplinary tumor boards should be strongly encouraged.

The effect of the COVID pandemic lockdown measures on surgical emergencies: experience and lessons learned from a Greek tertiary hospital.

BACKGROUND: The COVID-19 pandemic caused a rise in healthcare demands leading to significant restructuring of hospital emergency departments worldwide. The aim of the present study is twofold: firstly, to discern any differences in regard to reason for surgical emergency department (SED) attendance and hospital admission during the pandemic and pre-pandemic eras in Greece, and secondly, to assess the impact of the lockdown measures implemented during the pandemic on SED patient attendance. METHODS: Since the beginning of the COVID-19 pandemic in Greece (1 March 2020) and up to 15 December 2020, the charts of all adult patients arriving at the SED of the third surgical department of the "Attikon" University Hospital (a tertiary referral center for surgical and COVID-19 cases) were retrospectively reviewed and broken down in four periods reflecting two nationwide lockdown (period A 1/3/2020 to 30/4/2020 and period D 16/10/2020 to 15/12/2020) and two interim (period B 1/5/2020 to 15/6/2020 and period C 15/9/2020 to 30/10/2020) periods. Demographic and clinical data were compared to those obtained from the same time periods of the year 2019. RESULTS: The total number of patients attending the SED decreased by 35.9% during the pandemic (from 2839 total patients in 2019 to 1819 in 2020). During the first lockdown, there was statistically significant reduction of motor vehicle accidents (p=0.04) and torso injuries (p=0.01). Contrarily, the rate of head injuries (p<0.001) and abdominal pain (p=0.04) were significantly increased. The same effect was observed regarding the rate of hospital admissions (p=0.002), although in terms of absolute numbers, admissions remained unchanged. During the second lockdown, there was a reduction in the number of perianal abscess cases (p=0.04) and hernia-related problems (p=0.001). An increase in the rate of fall injuries was also demonstrable (p=0.02). Overall, application of the lockdown led to a significant decrease in minor (p<0.001) and torso (p=0.001) injuries. CONCLUSION: The burden of the new COVID-19 disease has left a noticeable imprint in the function of emergency departments worldwide. In Greece, SED attendance was significantly reduced during the pandemic, an effect that was even more pronounced during the lockdown implementation; nevertheless, the overall rate of hospital admissions remained the same, denoting that patient care was not altered.

A Case of Meningococcal and HSV-2 Meningitis in a Patient Being Treated with Ustekinumab for Pityriasis Rubra Pilaris.

Pityriasis rubra pilaris (PRP) is a rare chronic inflammatory papulosquamous dermatosis affecting both adults and children. Six subtypes of PRP have been described. Recently, the management of PRP with biologic immunosuppressive agents regularly used in psoriasis has been supported by several case reports and series. Ustekinumab is an anti-IL12/23 IgG1 kappa human monoclonal antibody. It has been approved for the treatment of Crohn's disease, plaque psoriasis, psoriatic arthritis and ulcerative colitis. It has also been reported to be effective as an off-label treatment for PRP. Current data are equivocal regarding infectious disease risk with ustekinumab administration. We describe a case of meningococcal and HSV-2 infection of the central nervous system in a patient being treated with ustekinumab for PRP. LEARNING POINTS: The administration of biologic immunosuppressive agents can result in severe life-threatening infections.Research is required on the infection potential of ustekinumab.Physicians should be aware of the possibility of infectious disease when prescribing biologic agents.Vaccination is essential in immunosuppressed adults.

Polycystin-1 induces activation of the PI3K/AKT/mTOR pathway and promotes angiogenesis in renal cell carcinoma.

In the present study we investigated the expression and the functional role of mechanosensitive polycystins in renal cell carcinoma (RCC). In 115 RCC patients we evaluated the protein expression of polycystin-1 (PC1), polycystin-2 (PC2), VEGF and protein components of the PI3K/Akt/mTOR pathway, which have been implicated both in RCC and polycystic kidney disease. PC1 and PC2 demonstrated reduced expression throughout the RCC tissue compared to the adjacent normal tissue. PC1 and PC2 revealed high expression when they were associated with higher grade and decreased 5-year survival respectively. PC1 and PC2 were positively correlated with p110γ subunit of PI3K and high PC1 expressing cells tended to display activation/phosphorylation of Akt. There was also a positive association between PC1 and VEGF expression, whereas PC1 augmented the tumor's microvascular network in stage IV carcinomas. In human RCC cells, functional inhibition of PC1 resulted in upregulation of the PI3K/Akt/mTOR pathway, enhanced cell proliferation and led to inhibition of cell migration. Conclusively, aberrant PC1 regulation is associated with increased angiogenesis and features of advanced disease in RCC tissues.

Blood-based analysis of 84 microRNAs identifies molecules deregulated in individuals with type-2 diabetes, risk factors for the disease or metabolic syndrome.

AIM: Micro-RNAs (miRNAs) are implicated in insulin-signaling and the development of type-2 diabetes (T2D). Their deregulated expression is mostly described in the pancreas, liver, skeletal muscle, or adipose tissue of diabetic animals. Relevant studies in humans are limited due to difficulties in accessing tissue-biopsies. Though, circulating miRNAs are indicators of organ-specific pathophysiological events and could potentially serve as disease biomarkers. We explored the profile of 84 T2D-related miRNAs in peripheral blood of subjects with or without the disease. METHODS: An RT-qPCR array screening 84 T2D-related miRNAs was applied in samples of T2D (n = 6) versus non-T2D (n = 6) subjects. The deregulated miRNAs were thereafter analyzed in peripheral blood samples of a validation cohort of 40 T2D and 37 non-T2D individuals [16 controls and 21 subjects with metabolic syndrome (Met-S) and/or T2D risk factors (T2D-RF)], using specific RT-qPCR assays. Correlations with clinicopathological parameters and risk factors were evaluated. RESULTS: Subjects with the disease displayed decreased levels of miR-214-3p, miR-24-3p and let-7f-5p, compared to those without. MiRNA levels correlated with serum insulin and HbA1c levels in individuals with T2D or Met-S/T2D-RF, and with higher BMI, dyslipidemia and family history in controls. CONCLUSIONS: Blood levels of miR-214-3p, miR-24-3p and let-7f-5p are down-regulated in T2D- and Met-S/T2D-RF subjects. Future studies are needed to evaluate their potential as disease biomarkers and elucidate the associated tissue-specific pathogenetic mechanisms.

Decreased expression of microRNAs targeting type-2 diabetes susceptibility genes in peripheral blood of patients and predisposed individuals.

AIM: Certain microRNA molecules (miRNAs) that target genes involved in beta-cell growth and insulin resistance are found deregulated in patients with type-2 diabetes mellitus (T2D) and correlate with its complications. However, the expression profile of miRNAs that regulate genes bearing T2D-related single-nucleotide polymorphisms has been hardly studied. We recently reported that the mRNA patterns of specific T2D-susceptibility genes are impaired in patients, and associate with disease parameters and risk factors. The aim of this study was to explore the levels of miRNAs that target those genes, in peripheral blood of patients versus controls. METHODS: A panel of 14 miRNAs validated to target the CDKN2A, CDK5, IGF2BP2, KCNQ1, and TSPAN8 genes, was developed upon combined search throughout the DIANNA TarBase v7.0, miRTarBase, miRSearch v3.0-Exiqon, miRGator v3.0, and miRTarget Link Human algorithms. Specifically developed poly(A)polyadenylation(PAP)-reverse transcription(RT)-qPCR protocols were applied in peripheral blood RNA samples from patients and controls. Possible correlations with the disease, clinicopathological parameters and/or risk factors were evaluated. RESULTS: T2D patients expressed decreased levels of let-7b-5p, miR-1-3p, miR-24-3p, miR-34a-5p, miR-98-5p, and miR-133a-3p, compared with controls. Moreover, these levels correlated with certain disease features including insulin and % HbA1c levels in patients, as well as BMI, triglycerides' levels and family history in controls. CONCLUSIONS: A T2D-specific expression profile of miRNAs that target disease-susceptibility genes is for the first time described. Future studies are needed to elucidate the associated transcription-regulatory mechanisms, perchance involved in T2D pathogenesis, and to evaluate the potential of these molecules as possible biomarkers for this disorder.

Blood-based analysis of type-2 diabetes mellitus susceptibility genes identifies specific transcript variants with deregulated expression and association with disease risk.

Despite significant progress by genome-wide association studies, the ability of genetic variants to conduce to the prediction or prognosis of type-2 diabetes (T2D) is weak. Expression analysis of the corresponding genes may suggest possible links between single-nucleotide polymorphisms and T2D phenotype and/or risk. Herein, we investigated the expression patterns of 24 T2D-susceptibility genes, and their individual transcript variants (tv), in peripheral blood of T2D patients and controls (CTs), applying RNA-seq and real-time qPCR methodologies, and explore possible associations with disease features. Our data revealed the deregulation of certain transcripts in T2D patients. Among them, the down-regulation of CAPN10 tv3 was confirmed as an independent predictor for T2D. In patients, increased expression of CDK5 tv2, CDKN2A tv3 or THADA tv5 correlated positively with serum insulin levels, of CDK5 tv1 positively with % HbA1c levels, while in controls, elevated levels of TSPAN8 were associated positively with the presence of T2D family history. Herein, a T2D-specific expression profile of specific transcripts of disease-susceptibility genes is for the first time described in human peripheral blood. Large-scale studies are needed to evaluate the potential of these molecules to serve as disease biomarkers.

Circulating adipokines and mRNA expression in adipose tissue and the placenta in women with gestational diabetes mellitus.

Maternal adipose tissue and the placenta secrete various molecules commonly called adipokines such as chemerin, omentin-1, visfatin, adiponectin, and leptin that are important players in the pathogenesis of insulin resistance. Gestational diabetes mellitus (GDM) is defined as a state of glucose intolerance characterized by ß-cell dysfunction and insulin resistance. To examine whether circulating adipokines and their mRNA expression in the adipose tissue and the placenta are altered in GDM pregnancy, we compared 15 GDM women [obese (BMI > 30) and non-obese (BMI < 30)] to 23 NGT (normal glucose tolerance) women [obese and non-obese], at the time of the Cesarean section. Circulating chemerin and leptin were higher (p = 0.009 and p = 0.005, respectively) and circulating omentin-1, visfatin, as well as the adiponectin/leptin ratio were lower (p = 0.039, p = 0.007 and p = 0.011, respectively) in GDM-obese compared to NGT-non-obese women. Chemerin and leptin correlated positively with BMI and HOMA-IR and omentin-1 correlated negatively with BMI. Serum TNF-α was significantly elevated in all obese compared to non-obese pregnant women and correlated positively with BMI. Adiponectin levels were reduced -although not significantly- in GDM- and NGT-obese women compared to their non-obese counterparts. Resistin, RPB4 and IL-6 levels did not differ significantly between groups. Chemerin mRNA expression in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) was significantly higher compared to placenta in all women (6-to 24-times, p < 0.05). Chemerin-VAT mRNA expression in GDM-obese tended to be significantly higher compared to NGT-non-obese women (3-times, p = 0.005). Omentin-1 mRNA expression was significantly higher in VAT compared to SAT (50- to 100-times, p < 0.01) and its expression in placenta was negligible in all women. Although, leptin was expressed significantly higher in SAT compared to VAT and the placenta in all women (5- to 46-times, p < 0.05), only its mRNA expression in VAT of obese (GDM and NGT) differed significantly when compared to NGT-non-obese women (3-times higher, p < 0.02). Visfatin mRNA expression was comparable in all tissues. In conclusion, chemerin and leptin are elevated and omentin-1 and visfatin levels are decreased in GDM women complicated by obesity. This finding together with the positive association of chemerin and leptin with markers of insulin resistance, suggests that these adipokines and more especially chemerin and leptin accompanied by their adipose tissue expression could contribute to the increased insulin resistance and low grade inflammation that characterizes GDM-obese women.

Alterations in Plasma Triglyceride Concentrations Following Two Oral Meals with Different Fat Content in Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Enhanced postprandial lipaemia has been reported in patients with obesity, hypertension, metabolic syndrome and type 2 diabetes mellitus (T2DM). We compared 2 oral fat meal tests (LIPOLD: 149g of fat, 56g of carbohydrates and 11.7g of proteins administrated per 2m2 of body surface) and LIPOTEST: 75g of fat, 25g of carbohydrates and 10g of protein with the addition of 15g common sugar) with regard to changes in triglycerides (TGs) as well as other cardiometabolic parameters between baseline and 4 h after the meals. METHODS: We studied 21 men [median age (interquartile range; IQR) = 65 (16) years] with well-controlled T2DM [median glycated haemoglobin (HbA1c) (IQR) = 6.6 (0.9) %]. All participants performed the meals with 1 week interval between the 2 meals. RESULTS: Median (IQR) TG differences in mg/dl were 86 (100) and 46 (60) for LIPOLD and LIPOTEST meals, respectively, whereas the % differences in TGs were 105 (105) and 48 (55), respectively. The differences (in mg/dl and %) between TGs before ingesting the test meal and after 4h were significant for both LIPOLD and LIPOTEST meals (p = 0.003 for mg/dl differences and p = 0.005 for % differences). Patients who had a positive response to the LIPOLD meal (i.e. TGs > 220 mg/dl at 4 h) also had increased postprandial TGs with LIPOTEST. The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) correlated with TG differences (in mg/dl) following the LIPOLD meal consumption (Spearman's rho = (+) 0.527, p = 0.02). C-peptide correlated with TG differences (in mg/dl) following the LIPOTEST meal consumption (Spearman's rho = (+) 0.538, p = 0.032). There were no differences in TGs and glucose response postprandially in both testing meals according to body mass index (except for TGs between tertile 21.3-24.5 and 25-26.8 kg/m2, p=0.046, in LPOTEST group) and body surface area. CONCLUSION: An oral fat tolerance test (OFTT), which contains 75g fat, and represents the everyday habits of Western societies, could provide additional information regarding the postprandial state of the individuals with well-controlled T2DM. The consumption of meals with very high fat content may lead to over diagnosing PPL. TG differences after the consumption of a high fat meal correlated with HOMA-IR. This may be useful to evaluate the role of HOMA-IR in T2DM patients. A standardized the OFTT will help clinicians to better define postprandial TG abnormalities, leading to more appropriate therapeutic options to improve postprandial dysmetabolism.

Plasma Glial Fibrillary Acidic Protein in the Differential Diagnosis of Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Plasma GFAP (glial fibrillary acidic protein) has recently emerged as a potential biomarker for the differentiation of acute intracerebral hemorrhage (ICH) from acute ischemic stroke (AIS). We prospectively assessed the diagnostic accuracy of GFAP in the differential diagnosis of ICH. METHODS: Consecutive patients presenting to the emergency department within 6 hours from symptom onset were evaluated. All patients underwent extensive diagnostic work-up and were classified according to discharge diagnosis in AIS, ICH, subarachnoid hemorrhage, and stroke mimics. GFAP was also measured in healthy volunteers (controls). Baseline stroke severity was evaluated using National Institutes of Health Stroke Scale. Receiver operating characteristic curve analysis was used to identify the optimal cutoff point for the differentiation between subgroups. Correlation analyses of GFAP plasma concentrations with baseline National Institutes of Health Stroke Scale and onset to sampling time were performed with the nonparametric Spearman rank test and fractional polynomial regression, respectively. RESULTS: Our study population consisted of 270 individuals (AIS: 121, ICH: 34, stroke mimics: 31, subarachnoid hemorrhage: 5, controls: 79). No differences on baseline stroke severity and onset to sampling time were detected between AIS and ICH. Higher median plasma GFAP values were documented in ICH compared with AIS, stroke mimics, and controls (P<0.001). Receiver operating characteristic analysis highlighted a cutoff value of 0.43 ng/mL as the optimal threshold for the differentiation between ICH and AIS (sensitivity: 91%, specificity: 97%). No association was detected between plasma GFAP concentrations and baseline stroke severity for both AIS (P=0.515) and ICH (P=0.387). In the fractional polynomial analysis, the association between GFAP concentration and onset to sampling time was best described by a J-shaped curve for AIS and an inverted U-shaped curve for ICH, with a peak at 2 hours. CONCLUSIONS: Plasma GFAP seems to be a sensitive and specific biomarker for the differentiation of ICH from both AIS and other acute neurological disorders, with the optimal diagnostic yield being present in the second hour from symptom onset.

Updated risk factors should be used to predict development of diabetes.

AIMS: Predicting incident diabetes could inform treatment strategies for diabetes prevention, but the incremental benefit of recalculating risk using updated risk factors is unknown. We used baseline and 1-year data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial to compare diabetes risk prediction using historical or updated clinical information. METHODS: Among non-diabetic participants reaching 1year of follow-up in NAVIGATOR, we compared the performance of the published baseline diabetes risk model with a "landmark" model incorporating risk factors updated at the 1-year time point. The C-statistic was used to compare model discrimination and reclassification analyses to demonstrate the relative accuracy of diabetes prediction. RESULTS: A total of 7527 participants remained non-diabetic at 1year, and 2375 developed diabetes during a median of 4years of follow-up. The C-statistic for the landmark model was higher (0.73 [95% CI 0.72-0.74]) than for the baseline model (0.67 [95% CI 0.66-0.68]). The landmark model improved classification to modest (<20%), moderate (20%-40%), and high (>40%) 4-year risk, with a net reclassification index of 0.14 (95% CI 0.10-0.16) and an integrated discrimination index of 0.01 (95% CI 0.003-0.013). CONCLUSIONS: Using historical clinical values to calculate diabetes risk reduces the accuracy of prediction. Diabetes risk calculations should be routinely updated to inform discussions about diabetes prevention at both the patient and population health levels.

Vascular risk factors and Alzheimer's disease pathogenesis: are conventional pharmacological approaches protective for cognitive decline progression?

Alzheimer's disease (AD) is the most common cause of dementia, accounting for more than half of cases with cognitive impairment. With numbers of patients expected to rise sharply over the following years in parallel with the ageing of population, there is intense clinical interest in discovering modifiable risk factors that may contribute to the increasing prevalence of AD. Accumulating data from in vitro and epidemiological studies have highlighted the vascular component of AD and raised hope that treatment of vascular risk factors could eventually lead to primary prevention of AD. Among all the possible pathologic processes that have been tested for an association with AD, diabetes, hypertension and dyslipidemia are the most prominent. Here, we will briefly review the data highlighting a potential correlation of these diseases with AD. Then, we will present observational studies and clinical trials that assessed the impact of their respective approved medical therapies on AD incidence. We conclude by providing clinical information for the physician on potentially effective and non-effective medical treatments. Further research is ongoing and time will show whether AD will cease to be considered a pure, non-preventable neurodegenerative process or whether vascular risk factor management may also result in primary AD prevention.

Cytokines, diabetes mellitus and psychopathology: a challenging combination.

OBJECTIVES: The aim of this study was to investigate the association of IL-6, IL-12, and TNF-α with trait and state psychological factors in type 2 diabetic patients. DESIGN: Patients were divided in two groups. Group A consisted of 86 controlled diabetic patients (HbA1c<7) and the Group B consisted of 45 uncontrolled diabetic patients (HbA1c ≥ 7). SETTINGS: During the initial phase of the study (T0), blood samples were taken for measuring IL-6, IL-12 and TNF-α serum levels as well as a battery of psychometric instruments. One year later (T1), the uncontrolled diabetic patients were re-evaluated with the use of the same psychometric instruments and with the identical blood analysis. RESULTS: The average values of tnf-α were significantly different among controlled (7.73 ± 5.51) and uncontrolled patients (9.29 ± 4.52) at a significance level of 5% (p=0.009). Controlled diabetic patients show a statistically significant relationship between IL-6 and neuroticism (rp=0.303, p=0.010), and between IL-12 and psychotism, (rsp=0.382, p=0.001). Controlled diabetic patients show a statistically significant relationship between IL-12 and the act out hostility (rsp=-0.307, p=0.009). The scores of the psychometric tests differ significantly between the first and second evaluation. Acting out hostility and the direction of hostility increased when HbA1c values fell below the threshold of 7, while the total hostility index, as well as all other scales, dropped when patients controlled their metabolic profile. CONCLUSIONS: The present results provide evidence that IL-6, IL-12 and TNF-α are closely related to the course and treatment of type 2 diabetes.

Endothelial progenitor cells as a cardiometabolic risk factor marker in prediabetes.

OBJECTIVE: Endothelial progenitor cells (EPCs) have recently been considered as a potential novel marker of vascular integrity, atherosclerosis and cardiovascular risk. This study was performed to investigate the main determinants of EPC levels in individuals with prediabetes. DESIGN: Thirty-nine participants with newly diagnosed prediabetes were enrolled. Flow cytometric analysis was used to quantify EPCs (CD34+CD133+VEGFR-2+). Traditional risk factors, high-sensitivity C-reactive protein (hs-CRP), homeostasis model assessment of insulin resistance (HOMA-IR) and anthropometric parameters, including ultrasonographic-determined visceral and subcutaneous fat, were recorded. RESULTS: In univariate analysis, EPC levels significantly correlated with waist circumference (p=0.017), mean arterial pressure (p=0.009), total cholesterol (p=0.003), hs-CRP (p=0.006), HOMA-IR (p=0.031) and visceral fat (p=0.040). However, in stepwise multivariate ordinal logistic regression analysis, only visceral fat retained its statistical significance (OR=0.79, 95%Cl:0.64-0.98, p=0.032). CONCLUSIONS: Visceral fat seems to be the main determinant of EPC levels in individuals with prediabetes and to form a plausible link between mild metabolic abnormalities, cardiovascular risk and vascular homeostasis process.

Association of lean body mass with cardiometabolic risk factors in healthy postmenopausal women.

OBJECTIVE: Aim of this study was to investigate the association of total and regional lean body mass (LBM) with cardiometabolic risk factors in healthy obese and nonobese postmenopausal women. METHODS: A total of 150 postmenopausal women (age 54 ± 7 years, BMI 29.6 ± 5.8 kg/m2) underwent a comprehensive assessment of cardiometabolic risk, including metabolic syndrome (MS). Body composition analysis was performed with Dual-energy X-ray Absorptiometry, and multiple height-adjusted indices of total and regional LBM were evaluated. RESULTS: After controlling for age, diet, physical activity, and total fat mass, most indices of total, central, and peripheral LBM displayed significant positive correlations with cardiometabolic risk factors. Most associations were no longer significant after controlling for waist circumference, with the only exception of lean mass in the arms, which remained significantly associated with the presence and severity of MS (number of MS abnormalities), independently of central adiposity. A significant additive interaction was found between lean mass in the arms and waist circumference in increasing the prevalence of MS. CONCLUSIONS: LBM is unfavorably associated with cardiometabolic risk factors in healthy postmenopausal women. Whether LBM, especially in arms, is associated with cardiometabolic health independently of central fat distribution in postmenopausal women, merits further investigation.