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BackgroundThe death toll of COVID-19 topped 170,000 in Europe by the end of May 2020. COVID-19 has caused an immense psychological burden on the population, especially among doctors and nurses who are faced with high infection risks and increased workload. ObjectiveThe aim of this study was to compare the mental health of medical professionals with nonmedical professionals in different European countries during the COVID-19 pandemic. We hypothesized that medical professionals, particularly those exposed to COVID-19 at work, would have higher levels of depression, anxiety, and stress. We also aimed to determine their main stressors and most frequently used coping strategies during the crisis. MethodsA cross-sectional online survey was conducted during peak COVID-19 months in 8 European countries. The questionnaire included demographic data and inquired whether the participants were exposed to COVID-19 at work or not. Mental health was assessed via the Depression Anxiety Stress Scales32 (23.53)–21 (DASS-21). A 12-item checklist on preferred coping strategies and another 23-item questionnaire on major stressors were completed by medical professionals. ResultsThe sample (N=609) consisted of 189 doctors, 165 nurses, and 255 nonmedical professionals. Participants from France and the United Kingdom reported experiencing severe/extremely severe depression, anxiety, and stress more often compared to those from the other countries. Nonmedical professionals had significantly higher scores for depression and anxiety. Among medical professionals, no significant link was reported between direct contact with patients with COVID-19 at work and anxiety, depression, or stress. “Uncertainty about when the epidemic will be under control” caused the most amount of stress for health care professionals while “taking protective measures” was the most frequently used coping strategy among all participants. ConclusionsCOVID-19 poses a major challenge to the mental health of working professionals as a considerable proportion of our participants showed high values for depression, anxiety, and stress. Even though medical professionals exhibited less mental stress than nonmedical professionals, sufficient help should be offered to all occupational groups with an emphasis on effective coping strategies.

Mild cognitive impairment (MCI) is recognized as a prodromal phase of dementing disorders, and it has been suggested that oxidative stress may play a role in the pathogenesis of Alzheimer's disease (AD), and in predicting progression of MCI to AD. In the present article, on the basis of an increasing body of evidence from cross-sectional and longitudinal studies, we discussed the issue of the possible impact of antioxidant compounds from diet and supplementation on MCI and its progression to AD. [ABSTRACT FROM AUTHOR]

Objective: The authors investigated the relationship of metabolic syndrome (MetS) and its individual components with incident dementia in a prospective population-based study with a 3.5-year follow-up.Methods: A total of 2097 participants from a sample of 5632 subjects (65-84 years old) from the Italian Longitudinal Study on Ageing were evaluated. MetS was defined according to the Third Adults Treatment Panel of the National Cholesterol Education Program criteria. Dementia, Alzheimer disease (AD) and vascular dementia (VaD) were classified using current published criteria.Results: MetS subjects (N=918) compared with those without MetS (N=1179) had an increased risk for VaD (1.63% vs 0.85%, adjusted hazard ratio (HR) 3.71, 95% CI 1.40 to 9.83). After excluding 338 subjects with baseline undernutrition, MetS subjects compared with those without MetS had an elevated risk of VaD (adjusted HR, 3.82; 95% CI 1.32 to 11.06). Moreover, those with MetS and high inflammation had a still further higher risk of VaD (multivariate adjusted HR, 9.55; 95% CI 1.17 to 78.17) compared with those without MetS and high inflammation. On the other hand, those with MetS and low inflammation compared with those without MetS and low inflammation did not exhibit a significant increased risk of VaD (adjusted HR, 3.31, 95% CI 0.91 to 12.14). Finally, a synergistic MetS effect versus its individual component effects was verified on the risk of VaD.Conclusion: In our population, MetS subjects had an elevated risk of VaD that increased after excluding patients with baseline undernutrition and selecting MetS subjects with high inflammation. [ABSTRACT FROM AUTHOR]

Drugs currently used to treat Alzheimer's Disease (AD) have limited therapeutic value and do not affect the main neuropathological hallmarks of the disease, i.e., senile plaques and neurofibrillar tangles. Senile plaques are mainly formed of beta-amyloid (Abeta), a 42-aminoacid peptide. Neurofibrillar tangles are composed of paired helical filaments of hyperphosphorylated tau protein. New, potentially disease-modifying, therapeutic approaches are targeting Abeta and tau protein. Drugs directed against Abeta include active and passive immunization, that have been found to accelerate Abeta clearance from the brain. The most developmentally advanced monoclonal antibody directly targeting Abeta is bapineuzumab, now being studied in a large Phase III clinical trial. Compounds that interfere with proteases regulating Abeta formation from amyloid precursor protein (APP) are also actively pursued. The discovery of inhibitors of beta-secretase, the enzyme that regulates the first step of the amyloidogenic metabolism of APP, has been revealed to be particularly difficult due to inherent medicinal chemistry problems, and only one compound (CTS-21166) has reached clinical testing. Conversely, several compounds that inhibit gamma-secretase, the pivotal enzyme that generates Abeta, have been identified, the most advanced being LY-450139 (semagacestat), now in Phase III clinical development. Compounds that stimulate alpha-secretase, the enzyme responsible for the non-amyloidogenic metabolism of APP, are also being developed, and one of them, EHT-0202, has recently entered Phase II testing. Potent inhibitors of Abeta aggregation have also been identified, and one of such compounds, PBT-2, has provided encouraging neuropsychological results in a recently completed Phase II study. Therapeutic approaches directed against tau protein include inhibitors of glycogen synthase kinase- 3 (GSK-3), the enzyme responsible for tau phosphorylation and tau protein aggregation inhibitors. NP-12, a promising GSK-3 inhibitor, is being tested in a Phase II study, and methylthioninium chloride, a tau protein aggregation inhibitor, has given initial encouraging results in a 50-week study. With all these approaches on their way, the hope for disease-modifying therapy in this devastating disease may become a reality in the next 5 years. [ABSTRACT FROM AUTHOR]

In the last decade, advances in understanding the neurobiology of Alzheimer's disease (AD) have translated into an increase in clinical trials assessing various potential AD treatments. At present, drugs used for the treatment of AD only slightly delay the inevitable symptomatic progression of the disease and do not affect the main neuropathological hallmarks of the disease, i.e. senile plaques and neurofibrillary tangles. Brain accumulation of oligomeric species of beta-amyloid (A beta) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being made to identify drugs able to interfere with proteases regulating A beta formation from amyloid precursor protein (APP). Compounds that stimulate alpha-secretase, the enzyme responsible for non-amyloidogenic metabolism of APP, are being developed and one of these, EHT-0202, has recently commenced evaluation in a phase II study. The discovery of inhibitors of beta-secretase (memapsin-2, beta-amyloid cleaving enzyme-1 [BACE-1]), the enzyme that regulates the first step of amyloidogenic APP metabolism, has proved to be particularly difficult because of inherent medicinal chemistry issues and only one compound (CTS-21166) has proceeded to clinical testing. Conversely, several compounds that inhibit gamma-secretase, the pivotal enzyme that generates A beta, have been identified, the most advanced being LY-450139 (semagacestat), presently in phase III clinical development. There has been considerable disappointment over the failure of a phase III study of tarenflurbil, a compound believed to modulate the activity of gamma-secretase, after encouraging phase II findings. Nevertheless, other promising gamma-secretase modulators are being developed and are approaching clinical testing. All these therapeutic approaches increase the hope of slowing the rate of decline in patients with AD and modifying the natural history of this devastating disease within the next 5 years. [ABSTRACT FROM AUTHOR]

BACKGROUND: Subacromial impingement syndrome (SAIS) is a painful condition resulting from the entrapment of anatomical structures between the anteroinferior corner of the acromion and the greater tuberosity of the humerus. OBJECTIVE: The aim of this study was to evaluate the short-term effectiveness of high-intensity laser therapy (HILT) versus ultrasound (US) therapy in the treatment of SAIS. DESIGN: The study was designed as a randomized clinical trial. SETTING: The study was conducted in a university hospital. PATIENTS: Seventy patients with SAIS were randomly assigned to a HILT group or a US therapy group. INTERVENTION: Study participants received 10 treatment sessions of HILT or US therapy over a period of 2 consecutive weeks. MEASUREMENTS: Outcome measures were the Constant-Murley Scale (CMS), a visual analog scale (VAS), and the Simple Shoulder Test (SST). RESULTS: For the 70 study participants (42 women and 28 men; mean [SD] age=54.1 years [9.0]; mean [SD] VAS score at baseline=6.4 [1.7]), there were no between-group differences at baseline in VAS, CMS, and SST scores. At the end of the 2-week intervention, participants in the HILT group showed a significantly greater decrease in pain than participants in the US therapy group. Statistically significant differences in change in pain, articular movement, functionality, and muscle strength (force-generating capacity) (VAS, CMS, and SST scores) were observed after 10 treatment sessions from the baseline for participants in the HILT group compared with participants in the US therapy group. In particular, only the difference in change of VAS score between groups (1.65 points) surpassed the accepted minimal clinically important difference for this tool. LIMITATIONS: This study was limited by sample size, lack of a control or placebo group, and follow-up period. CONCLUSIONS: Participants diagnosed with SAIS showed greater reduction in pain and improvement in articular movement functionality and muscle strength of the affected shoulder after 10 treatment sessions of HILT than did participants receiving US therapy over a period of 2 consecutive weeks. [ABSTRACT FROM AUTHOR]

Currently available epidemiological evidence suggested that an increase of saturated fatty acids (SFA) could have negative effects on cognitive functions, while increased polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA) may be protective against cognitive decline. In a Southern Italian elderly population from the Italian Longitudinal Study on Aging (ILSA), a clear reduction of risk of age-related cognitive decline (ARCD) has been found with elevated intake of PUFA and MUFA. Furthermore, in the ELSA, while dietary fatty acids intakes were not associated with incident mild cognitive impairment (MCI), high PUFA intake appeared to have borderline non-significant trend for a protective effect against the development of MCI. These epidemiological findings on predementia syndromes, i.e. MCI or ARCD, together with a recent randomised controlled trial on a possible effect on cognitive and depressive symptoms of -3 PUFA supplementation in patients with very mild AD, suggested a possible role of fatty acids intake in maintaining adequate cognitive functioning and possibly in preventing or delaying the onset of dementia. [ABSTRACT FROM AUTHOR]

Even during the third wave of the COVID-19 pandemic health professionals were facing mental health challenges. The aim of this study was to examine the mental health of doctors, nurses and other professional groups in Europe and to identify differences between the professional groups. We conducted a cross-sectional online survey in 8 European countries. We asked for demographic data, whether the participants were exposed to COVID-19 at work, for main information sources about the pandemic, the Depression Anxiety Stress Scales (DASS-21), and major stressors. A MANCOVA was carried out to find predictors of mental health among health care professionals. The sample (N = 1398) consisted of 237 physicians, 459 nurses, and 351 other healthcare professionals and 351 non-medical professionals with no direct involvement in patient care. The mean mental health of all groups was affected to a mild degree. Major predictors for depression and anxiety were the profession group with higher scores especially in the group of the nurses and working directly with COVID-patients. In the third wave of the COVID-19 pandemic, the psychological burden on health professionals has remained high, with being nurse and working directly with COVID19 patients being particular risk factors for mental distress. We found as a main result that nurses scored significantly higher on depression and anxiety than practitioners., (© 2024. The Author(s).)

Lactate represents the main product of pyruvate reduction catalyzed by the lactic dehydrogenase family of enzymes. Cancer cells utilize great quantities of glucose, shifting toward a glycolytic metabolism. With the contribution of tumor stromal cells and under hypoxic conditions, this leads toward the acidification of the extracellular matrix. The ability to shift between different metabolic pathways is a characteristic of breast cancer cells and is associated with an aggressive phenotype. Furthermore, the preliminary scientific evidence concerning the levels of circulating lactate in breast cancer points toward a correlation between hyperlactacidemia and poor prognosis, even though no clear linkage has been demonstrated. Overall, lactate may represent a promising metabolic target that needs to be investigated in breast cancer.

Context: The assessment of decision-making ability of older adults with cognitive impairment is a complex challenge that geriatricians often face in relation to risk-taking situations (driving, aging in place, financial decisions, etc.). However, there are no clear and consensual practice guidelines. An overview of current practices and needs seemed necessary., Methods: We co-created and conducted an online survey to describe practice and knowledge, among European geriatricians. The survey was structured in 3 parts: a description of the professional's practice regarding cognitive impairment, a specific questionnaire about everyday risky decision-making evaluation and an investigation of the clinician's knowledge about relevant ethical and legal recommendations. Each part consisted of both multiple choice and open questions, analyzed through descriptive statistics and qualitative analysis methods., Results: Based on the responses of 123 geriatricians across Europe, our survey showed that clinical interview is the cornerstone of geriatric assessment of decision-making ability of patients with mild to moderate dementia. When faced with risk-taking dilemma situations, geriatricians tend to favor a context of safety above autonomy, but they can support risky decision-making if it is consistent with the patient's previous lifestyle, depending on the degree of risk to self and others, on the decision-making ability assessed, and if there is some form of shared decision-making., Conclusion: Assessing decision-making ability is challenging for geriatricians, who in our study relied more on their clinical interview and global cognitive tests than more in-depth evaluations. Supporting independent decision-making, when associated with risk-taking, requires better detection and anticipation shared with the patient environment., (© 2023. The Author(s), under exclusive licence to European Geriatric Medicine Society.)

Background: The COVID-19 pandemic severely affected everyday life and working conditions for most Europeans, particularly health care professionals (HCPs). Over the past 3 years, various policies have been implemented in various European countries. Studies have reported on the worsening of mental health, work-related stress, and helpful coping strategies. However, having a closer look is still necessary to gain more information on the psychosocial stressors and unmet needs of HCPs as well as nonmedical staff., Objective: This study aimed to obtain quantitative information on job-related stressors of physicians and nurses and the coping strategies of HCPs and nonmedical staff at 2 periods of the COVID-19 pandemic. By further analyzing qualitative comments, we wanted to gain more information on the psychosocial stressors and unmet needs of HCPs as well as nonmedical staff on different levels of experience., Methods: A cross-sectional survey was conducted at 2 time points during the COVID-19 pandemic in several European countries. The first study period (T1) lasted between April 1 and June 20, 2020, and the second study period (T2) lasted between November 25, 2021, and February 28, 2022. On a quantitative level, we used a questionnaire on stressors for physicians and nurses and a questionnaire on coping strategies for HCPs and nonmedical staff. Quantitative data were descriptively analyzed for mean values and differences in stressors and coping strategies. Qualitative data of free-text boxes of HCPs and nonmedical staff were analyzed via thematic analysis to explore the experiences of the individuals., Results: T1 comprised 609 participants, and T2 comprised 1398 participants. Overall, 296 participants made 438 qualitative comments. The uncertainty about when the pandemic would be controlled (T1: mean 2.28, SD 0.85; T2: mean 2.08, SD 0.90) and the fear of infecting the family (T1: mean 2.26, SD 0.98; T2: mean 2.02, SD 1.02) were the most severe stressors identified by physicians and nurses in both periods. Overall, the use of protective measures (T1: mean 2.66, SD 0.60; T2: mean 2.66, SD 0.60) and acquiring information about COVID-19 (T1: mean 2.29, SD 0.82; T2: mean 1.99, SD 0.89) were identified as the most common coping strategies for the entire study population. Using thematic analysis, we identified 8 themes of personal experiences on the micro, meso, and macro levels. Measures, working conditions, feelings and emotions, and social climate were frequently mentioned topics of the participants. In T1, feelings of isolation and uncertainty were prominent. In T2, feelings of exhaustion were expressed and vaccination was frequently discussed. Moreover, unmet psychosocial needs were identified., Conclusions: There is a need for improvement in pandemic preparedness. Targeted vocational education measures and setting up of web-based mental health support could be useful to bridge gaps in psychosocial support needs in future crises., (©Svenja Hummel, Ina Michelsen, Ali Zafar, Steffen Moritz, Charles Benoy, Cédric Lemogne, Rosa Almeida, Raquel Losada, Oscar Ribeiro, Vincenza Frisardi, Ilaria Tarricone, Silvia Ferrari, Frieder Dechent, Christian G Huber, Steffi Weidt, Gwendolyn Mayer, Jobst-Hendrik Schultz. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 06.09.2023.)

Background: Older adults with mood disorders constitute a heterogeneous group in a complex spectrum interlinked with physical comorbidities. Worldwide, Bipolar disorders in older people (OABD) remain underestimated and underdiagnosed. OABD is challenging in the clinical setting and is associated with adverse outcomes (increased risk of anti-social behaviour triggered by inappropriate drugs and increased incidence of health deficits, including cancer). This article aims to describe the state of the art of OABD in the Italian framework and provide a new field of research., Methods: We performed an overview of the literature, selecting our target population (over 65 years) and synthesising the main challenging issues. By exploiting the Italian database from the Minister of Health in 2021, we analysed epidemiological data in the age range 65-74 years and 75-84 years old., Results: Females showed the highest prevalence and incidence in both groups, with a regional difference across the country but more evident in the Autonomous Provinces of Bolzano and Trento for the 65-74 years range. Several projects recently focused on this topic, and the urgency to define better the epidemiological framework is mandatory., Conclusions: This study represented the first attempt to report the comprehensive Italian framework on OABD aimed at fostering research activities and knowledge.

Objective: To evaluate the impact of the COVID-19 pandemic on first and follow-up visits for cancer outpatients., Methods: This is a multicenter retrospective observational study involving three Comprehensive Cancer Care Centers (CCCCs): IFO, including IRE and ISG in Rome, AUSL-IRCCS of Reggio Emilia, and IRCCS Giovanni Paolo II in Bari) and one oncology department in a Community Hospital (Saint'Andrea Hospital, Rome). From 1 January 2020 and 31 December 2021, we evaluated the volume of outpatient consultations (first visits and follow-up), comparing them with the pre-pandemic year (2019). Results were analyzed by quarter according to the Rt (real-time indicator used to assess the evolution of the pandemic). IFO and IRCCS Giovanni Paolo II were "COVID-free" while AUSL-IRCCS RE was a "COVID-mixed" Institute. Depending on the Rt, Sain't Andrea Hospital experienced a "swinging" organizational pathway (COVID-free/ COVID-mixed)., Results: Regarding the "first appointments", in 2020 the healthcare facilities operating in the North and Center of Italy showed a downward trend. In 2021, only AUSL-IRCCS RE showed an upward trend. Regarding the "follow-up", only AUSL IRCCS RE showed a slight up-trend in 2020. In 2021, IFO showed an increasing trend, while S. Andrea Hospital showed a negative plateau. Surprisingly, IRCCS Giovanni Paolo II in Bari showed an uptrend for both first appointment and follow-ups during pandemic and late pandemic except for the fourth quarter of 2021., Conclusions: During the first pandemic wave, no significant difference was observed amongst COVID-free and COVID-mixed Institutes and between CCCCs and a Community Hospital. In 2021 ("late pandemic year"), it has been more convenient to organize COVID-mixed pathway in the CCCCs rather than to keep the Institutions COVID-free. A swinging modality in the Community Hospital did not offer positive results in term of visit volumes. Our study about the impact of COVID-19 pandemic on visit volume in cancer outpatients may help health systems to optimize the post-pandemic use of resources and improve healthcare policies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Frisardi, Brunetti, Abbinante, Ardigò, Caolo, Di Turi, Torsello, Napoli, Mancini, Belleudi, Addis, Di Bella, Ciliberto, Neri, Corsini, Ruggieri, Pollorsi and Silvestris.)

Background/rationale: Despite mounting evidence about delirium, this complex geriatric syndrome is still not well managed in clinical contexts. The aging population creates a very demanding area for innovation and technology in healthcare. For instance, an outline of an aging-friendly healthcare environment and clear guidance for technology-supported improvements for people at delirium risk are lacking. Objective: We aimed to foster debate about the importance of technical support in optimizing healthcare professional practice and improving the outcomes for inpatients' at delirium risk. We focused on critical clinical points in the field of delirium worthy of being addressed by a multidisciplinary approach. Methods: Starting from a consensus workshop sponsored by the Management Perfectioning Course based at the Marco Biagi Foundation (Modena, Italy) about clinical issues related to delirium management still not addressed in our healthcare organizations, we developed a requirements' analysis among the representatives of different disciplines and tried to formulate how technology could support the summaries of the clinical issues. We analyzed the national and international panorama by a PubMed consultation of articles with the following keywords in advanced research: "delirium", "delirium management", "technology in healthcare", and "elderly population". Results: Despite international recommendations, delirium remains underdiagnosed, underdetected, underreported, and mismanaged in the acute hospital, increasing healthcare costs, healthcare professionals' job distress, and poor clinical outcomes. Discussion: Although all healthcare professionals recognize delirium as a severe and potentially preventable source of morbidity and mortality for hospitalized older people, it receives insufficient attention in resource allocation and multidisciplinary research. We synthesized how tech-based tools could offer potential solutions to the critical clinical points in delirium management.

The outbreak of the coronavirus 2 disease 2019 (COVID-19) puts an enormous burden on healthcare systems worldwide. This may worsen outcomes in patients with severe chronic diseases such as cancer, autoimmune diseases, and immune deficiencies. In this critical situation, only a few available data exist, which do not allow us to provide practical guides for the treatment of oncological or immunocompromised patients. Therefore, a further step forward is needed, addressing the specific needs and demands of frail patients in the pandemic era. Here we aim to present a protocol of a study approved by an ethical committee named "CO.M.E.TA". CO.M.E.TA protocol is a network project involving six Italian institutions and its goals are: i) to measure and compare the impact of the pandemic on the access of cancer and immunocompromised patients to therapies in three Italian regions; ii) to assess how reorganizational measures put in place in these different institutions have impacted specific metrics of performance; iii) to establish a COVID-19 Biobank of biological samples from SARS-CoV-2 infected patients to be used to study immunological alterations in patients with immune frailty., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Silvestris, Belleudi, Addis, Pimpinelli, Morrone, Sciacchitano, Mancini, Garrisi, Costantini, Ciliberto, Frisardi and Piaggio.)

Metabolic syndrome (MetS) affects the population worldwide and results from several factors such as genetic background, environment and lifestyle. In recent years, an interplay among autophagy, metabolism, and metabolic disorders has become apparent. Defects in the autophagy machinery are associated with the dysfunction of many tissues/organs regulating metabolism. Metabolic hormones and nutrients regulate, in turn, the autophagy mechanism. Autophagy is a housekeeping stress-induced degradation process that ensures cellular homeostasis. High mobility group box 1 (HMGB1) is a highly conserved nuclear protein with a nuclear and extracellular role that functions as an extracellular signaling molecule under specific conditions. Several studies have shown that HMGB1 is a critical regulator of autophagy. This mini-review focuses on the involvement of HMGB1 protein in the interplay between autophagy and MetS, emphasizing its potential role as a promising biomarker candidate for the early stage of MetS or disease's therapeutic target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Frisardi, Matrone and Street.)

Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no cure and no effective diagnostic criteria. The greatest challenge in effectively treating AD is identifying biomarkers specific for each patient when neurodegenerative processes have not yet begun, an outcome that would allow the design of a personalised therapeutic approach for each patient and the monitoring of the therapeutic response during the treatment. We found that the excessive phosphorylation of the amyloid precursor protein (APP) Tyr 682 residue on the APP 682 YENPTY 687 motif precedes amyloid β accumulation and leads to neuronal degeneration in AD neurons. We proved that Fyn tyrosine kinase elicits APP phosphorylation on Tyr 682 residue, and we reported increased levels of APP Tyr 682 and Fyn overactivation in AD neurons. Here, we want to contemplate the possibility of using fibroblasts as tools to assess APP Tyr 682 phosphorylation in AD patients, thus making the changes in APP Tyr 682 phosphorylation levels a potential diagnostic strategy to detect early pathological alterations present in the peripheral cells of AD patients' AD brains.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Metabolic syndrome (MetS) has been found to be a risk factor for dementia, mild cognitive impairment, and its associated states. However, a definitive conclusion cannot be drawn from the available data. Discrepancies between the results are due to several factors, e.g., study design, heterogeneity of the population enrolled, reliability and sensitivity of detection tools for cognitive changes, cut-offs and criteria used to diagnose MetS, the outcome measures considered, MetS duration before the onset of cognitive decline, and also the analytical approach performed. Recently, a systematic review and meta-analysis including 19,522 subjects aged 59-85 years from 13 longitudinal population-based studies has been conducted to examine the association between MetS and longitudinal changes in cognitive functions. While a marginal significant association was found in the younger old group, this relationship was not observed in older group (>70 years). It is not yet clear how age can influence this relationship. Apart from methodological issues, other biological factors are likely involved in this direction reversal.

Midlife elevated blood pressure and hypertension contribute to the development of Alzheimer's disease (AD) and overall dementia. We sought to estimate whether angiotensin-converting enzyme inhibitors (ACE-Is) reduced the risk of developing mild cognitive impairment (MCI) in cognitively normal individuals. In the Italian Longitudinal Study on Aging, we evaluated 1,445 cognitively normal individuals treated for hypertension but without congestive heart failure from a population-based sample from eight Italian municipalities with a 3.5-year follow-up. MCI was diagnosed with current clinical criteria. Dementia, AD, and vascular dementia were diagnosed based on DSM-IIIR criteria, NINCDS-ADRDA criteria, and ICD-10 codes. Among 873 hypertension-treated cognitively normal subjects, there was no significant association between continuous exposure to all ACE-Is and risk of incident MCI compared with other antihypertensive drugs [hazard ratio (HR), 0.45, 95% confidence interval (CI), 0.16-1.28]. Captopril exposure alone did not significantly modify the risk of incident MCI (HR, 1.80, 95% CI, 0.39-8.37). However, the enalapril sub-group alone (HR, 0.17, 95% CI, 0.04 -0.84) or combined with the lisinopril sub-group (HR, 0.27, 95% CI, 0.08-0.96), another ACE-I structurally related to enalapril and with similar potency, were associated with a reduced risk of incident MCI. Study duration exposure to ACE-Is as a "class" was not associated with incident MCI in older hypertensive adults. However, within-class differences linked to different chemical structures and/or drug potencies may exist, with a possible effect of the enalapril and lisinopril sub-groups in reducing the risk of incident MCI.

Botulinum toxin type A (BTX-A) represents the gold standard therapy for focal spasticity after stroke, with low prevalence of complications, reversibility, and efficacy in reducing spastic hypertonia. Current guidelines suggest the employment of a dosage up to 600 units (U) of BTX-A to treat spasticity after stroke, to avoid important adverse effects and the development of antibodies against the neurotoxin. In recent years, NT 201, a new BTX-A free of complexing proteins, has been used for treating several movement disorders, showing safety and efficacy in upper limb spasticity. In a prospective, non-randomized, open-label study, we studied the efficacy and safety of higher doses of BTX-A NT 201 (up to 840 U) in 25 consecutive patients with upper and lower limb spasticity after stroke, evaluated at 30 and 90 days after injections. Before and after the treatment, the grade of spasticity, the disability, and spasticity-related pain were extensively measured. After 30 days of follow-up, a great reduction of spasticity and pain with improvement of disability was observed. The effects were still present at 90 days of follow-up. No major adverse events were observed. Higher doses of BTX-A NT 201 appeared to be safe and efficacious in patients with upper and lower limb spasticity after stroke. However, further investigations are needed to determine its reproducibility in larger case series or randomized clinical trials and to observe the absence of antibodies against the neurotoxin also after repeated injections.

Background: Frailty is a clinical syndrome generally associated with a greater risk for adverse outcomes such as falls, disability, institutionalization, and death. Cognition and dementia have already been considered as components of frailty, but the role of frailty as a possible determinant of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) has been poorly investigated. We estimated the predictive role of frailty syndrome on incident dementia and its subtypes in a nondemented, Italian, older population., Methods: We evaluated 2581 individuals recruited from the Italian Longitudinal Study on Aging sample population consisting of 5632 subjects aged 65 to 84 years and with a 3.9-year median follow-up. A phenotype of frailty according to a modified measurement of Cardiovascular Health Study criteria was operationalized. Dementia, AD, and VaD were classified using current published criteria., Results: Over a 3.5-year follow-up, 65 of 2581 (2.5%) older subjects, 16 among 252 frail individuals (6.3%), of which 9 were affected by VaD (3.6%), developed overall dementia. In a proportional hazards model, frailty syndrome was associated with a significantly increased risk of overall dementia (adjusted hazard ratio: 1.85; 95% confidence interval: 1.01-3.40) and, in particular, VaD (adjusted hazard ratio: 2.68; 95% confidence interval: 1.16-7.17). The risk of AD or other types of dementia did not significantly change in frail individuals in comparison with subjects without frailty syndrome., Conclusion: In our large population-based sample, frailty syndrome was a short-term predictor of overall dementia and VaD., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective: In several longitudinal studies, light-to-moderate drinking of alcoholic beverages has been proposed as being protective against the development of age-related changes in cognitive function, predementia syndromes, and cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia). However, contrasting findings also exist., Method: The English literature published in this area before September 2011 was evaluated, and information relating to the various factors that may impact upon the relationship between alcohol consumption and dementia or predementia syndromes is presented in the succeeding texts., Results: Light-to-moderate alcohol consumption may be associated with a reduced risk of incident overall dementia and AD; however, protective benefits afforded to vascular dementia, cognitive decline, and predementia syndromes are less clear. The equivocal findings may relate to many of the studies being limited to cross-sectional designs, restrictions by age or gender, or incomplete ascertainment. Different outcomes, beverages, drinking patterns, and study follow-up periods or possible interactions with other lifestyle-related (e.g., smoking) or genetic factors (e.g., apolipoprotein E gene variation) may all contribute to the variability of findings., Conclusion: Protective effects of moderate alcohol consumption against cognitive decline are suggested to be more likely in the absence of the AD-associated apolipoprotein E ε4 allele and where wine is the beverage. At present, there is no indication that light-to-moderate alcohol drinking would be harmful to cognition and dementia, and attempts to define what might be deemed beneficial levels of alcohol intake in terms of cognitive performance would be highly problematic and contentious., (Copyright © 2012 John Wiley & Sons, Ltd.)

Objective: Some patients receiving botulinum toxin type A therapy develop immunological resistance due to the production of neutralizing antibodies against the neurotoxin, thus partially or completely reducing the therapeutic effect., Case Report: We report here neurophysiological and clinical findings for a 58-year-old man treated with botulinum toxin type A for spasticity after ischaemic stroke, who became a secondary non-responder patient. Subsequent treatment with a different preparation of botulinum toxin type A had a great therapeutic effect on his spasticity. The muscles injected and the dosages were the same for each treatment, but evaluation with the Modified Ashworth Scale after treatment with the second preparation showed a reduction of approximately 2 points compared with the first examination. The clinical results were also supported by extensor digitorum brevis testing of the right muscle, which showed a reduction in compound muscle action potential, whereas it was unchanged in the non-injected muscle. No side-effects were reported, and after 1 year of treatment with this formulation clinical benefits were still evident., Conclusion: The neurophysiological and clinical results obtained in this patient suggest that switching therapy from a complexing protein-containing product to a product potentially free of complexing proteins, which has low immunogenicity, may be a viable therapeutic option in secondary non-responder patients.

The effectiveness of pulmonary rehabilitation (PR) has been recognized in national and international guidelines and highlighted by the National Institute of Clinical Excellence as one of the six key priorities for improving the care of chronic obstructive pulmonary disease (COPD) patients. PR is likely to be effective in bronchiectasis as it is in COPD. We evaluated the efficacy of PR in the management of bronchiectasis. Three outpatients affected by bronchiectasis, with cough, sputum production, dyspnea, and decreased exercise tolerance, were submitted to five months of PR program consisting in treadmill walking, cycle ergometry, breathing exercises, and postural drainage with clapping percussion-vibratory-shaking. In all patients, after PR, chest X-ray showed that the obstructive disease decreased with bronchial wall thickness reduction. This improvement facilitated the performance of breath actions increasing the exercise tolerance and quality of life, evaluated respectively with the 6-minute walk test, the SF36, and the RPE Borg scale. The improvements in both exercise capacity and health status observed at the end of the PR program were maintained in a 6-month follow-up after the cessation of training with also a reduction of acute bronchial exacerbations. These results highlighted the potential role of PR in patients with bronchiectasis, however further investigations are needed to identify the most eligible patients and to optimize the training programs to maintain long term benefit. Chest x-ray may represent a relevant instrument to observe the clinical improvement of these patients, also when spirometric values do not change significantly.

Cognition has already been considered as a component of frailty, and it has been demonstrated that it is associated with adverse health outcomes. We estimated the prevalence of frailty syndrome in an Italian older population and its predictive role on all-cause mortality and disability in nondemented subjects and in demented patients. We evaluated 2,581 individuals recruited from the Italian Longitudinal Study on Aging, a population-based sample of 5,632 subjects, aged 65-84 years old. Participants received identical baseline evaluation at the 1st survey (1992-1993) and were followed at 2nd (1995-1996) and 3rd survey (2000-2001). A phenotype of frailty according to partially modified measurement of Cardiovascular Health Study criteria was operationalized. The overall prevalence of frailty syndrome in this population-based study was 7.6% (95% confidence interval (CI) 6.55-8.57). Frail individuals noncomorbid or nondisable were 9.1% and 39.3%, respectively, confirming an overlap but not concordance in the co-occurrence among these conditions. Frailty was associated with a significantly increased risk of all-cause mortality over a 3-year follow-up (hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.52-2.60) and over a 7-year follow-up (HR 1.74, 95% CI 1.44-2.16), but with significant increased risk of disability only over a 3-year follow-up (HR 1.32, 95% CI 1.06-1.86 over a 3-year follow-up and HR 1.16, 95% CI 0.88-1.56 over a 7-year follow-up). Frail demented patients were at higher risk of all-cause mortality over 3- (HR 3.33, 95% CI 1.28-8.29) and 7-year follow-up periods (HR 1.89, 95% CI 1.10-3.44), but not of disability. Frailty syndrome was a short-term predictor of disability in nondemented older subjects and short- and long-term predictor of all-cause mortality in nondemented and demented patients.

The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic 'bodyweight/appetite/satiety set point,' resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer's disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer's disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer's disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders., (© Springer Basel AG 2011)

Solanezumab (LY2062430) is a humanized monoclonal antibody that binds to the central region of β-amyloid, a peptide believed to play a key role in the pathogenesis of Alzheimer's disease (AD). Eli Lilly & Co is developing an intravenous formulation of solanezumab for the treatment of mild-to-moderate AD. Acute and subchronic treatment with solanezumab of transgenic mice attenuated or reversed memory deficits with no effects on incidence or severity of cerebral amyloid angiopathy-associated microhemorrhages, a severe side effect associated with bapineuzumab, another monoclonal antibody. Phase II studies in AD patients have shown a good safety profile with encouraging indications on cerebrospinal and plasma biomarkers. The drug is currently being investigated in Phase III trials. While there is a strong hope that solanezumab may represent the first effective passive vaccine for AD treatment, skepticism still exists on the ability of the drug to slow the rate of deterioration in patients with fully established disease.

The exact mechanisms leading to Alzheimer's disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular β-amyloid (Aβ), peptide deposition (senile plaques) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decade, most of the efforts of the pharmaceutical industry were directed against the production and accumulation of Aβ. The most innovative of the pharmacological approaches was the stimulation of Aβ clearance from the brain of AD patients via the administration of Aβ antigens (active vaccination) or anti-Aβ antibodies (passive vaccination). Several active and passive anti-Aβ vaccines are under clinical investigation. Unfortunately, the first active vaccine (AN1792, consisting of preaggregate Aβ and an immune adjuvant, QS-21) was abandoned because it caused meningoencephalitis in approximately 6% of treated patients. Anti-Aβ monoclonal antibodies (bapineuzumab and solanezumab) are now being developed. The clinical results of the initial studies with bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E ε4 carriers), has raised concerns on the safety of these antibodies directed against the N-terminus of the Aβ peptide. Solanezumab, a humanized anti-Aβ monoclonal antibody directed against the midregion of the Aβ peptide, was shown to neutralize soluble Aβ species. Phase II studies showed a good safety profile of solanezumab, while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. Although some studies suggested that active immunization may be effective against tau in animal models of AD, very few studies regarding passive immunization against tau protein are currently available. The results of the large, ongoing Phase III trials with bapineuzumab and solanezumab will tell us if monoclonal anti-Aβ antibodies may slow down the rate of deterioration of AD. Based on the new diagnostic criteria of AD and on recent major failures of anti-Aβ drugs in mild-to-moderate AD patients, one could argue that clinical trials on potential disease-modifying drugs, including immunological approaches, should be performed in the early stages of AD.

Apolipoprotein E [ApoE, APOE (gene)] is a multifunctional protein of the lipid and lipoprotein transport system mainly involved in metabolism of dietary lipids. Its polymorphic variants are considered a genetic risk factor of cognitive impairment in several neurodegenerative disorders such as Lewy body dementia, Huntington's disease, and Alzheimer's disease, as well as in vascular dementia and cerebrovascular disease. The precise mechanism by which APOE affects neurodegeneration is still unclear. Epidemiological and experimental studies demonstrated an influence of APOE on metabolic parameters but, to the best of our knowledge, no data are available about the exact role in humans of the effect of APOE on metabolic-cognitive syndrome (MCS). The latter is a model of cognitive impairment linked to metabolic syndrome identifying a grey zone between metabolic disorders and neuropathological process driving late-life cognitive decline. Although it may be a daring project that does not reach a final conclusion because of disease complexity, I hope to elucidate whether APOE may have a prominent role in MCS, going beyond the simple addition of separate mechanisms already known.

Midlife hypertension is a risk factor for late onset Alzheimer's disease (AD) and it is one of the components of metabolic syndrome (MetS). Observational studies and some cardiovascular disease-related clinical trials suggest that antihypertensive treatment reduced the incidence and progression of AD. Calcium channel blockers (CCBs), one of the more commonly used treatments for hypertension, target voltage-gated calcium channels (VGCCs) which are found on neurons in the brain where calcium regulation is very important in both learning and memory. Amyloid-β (Aβ) peptide, one of the main pathological hallmarks of AD, causes increases to intracellular calcium via VGCCs, which in turn leads to further increases in Aβ production. Memantine, a current treatment used in AD, exerts some of its beneficial effects by blocking calcium entry into neurons. We explore the possibility of whether CCBs acting in the brain may delay the onset and progression of AD and thus may inform treatment regimes in people with MetS.