Anticancer drugs repurposed for Alzheimer’s disease: a systematic review

Background: The relationship between cancer and dementia is triggering growing research interest. Several preclinical studies have provided the biological rationale for the repurposing of specific anticancer agents in Alzheimer’s disease (AD), and a growing number of research protocols are testing their efficacy and safety/ tolerability in patients with AD. Methods: The aim of the present systematic review was to provide an overview on the repurposing of approved anticancer drugs in clinical trials for AD by considering both ongoing and completed research protocols in all phases. In parallel, a systematic literature review was conducted on PubMed, ISI Web, and the Cochrane Library to identify published clinical studies on repurposed anticancer agents in AD. Results: Based on a structured search on the ClinicalTrials.gov and the EudraCT databases, we identified 13 clinical trials testing 11 different approved anticancer agents (five tyrosine kinase inhibitors, two retinoid X receptor agonists, two immunomodulatory agents, one histone deacetylase inhibitor, and one monoclonal antibody) in the AD continuum. The systematic literature search led to the identification of five published studies (one phase I, three phase II, and one phase IIb/III) reporting the effects of antitumoral treatments in patients with mild cognitive impairment or AD dementia. The clinical findings and the methodological characteristics of these studies are described and discussed. Conclusion: Anticancer agents are triggering growing interest in the context of repurposed therapies in AD. Several clinical trials are underway, and data are expected to be available in the near future. To date, data emerging from published clinical studies are controversial. The promising results emerging from preclinical studies and identified research protocols should be confirmed and extended by larger, adequately designed, and high-quality clinical trials

Use of Biomarkers in Ongoing Research Protocols on Alzheimer's Disease

The present study aimed to describe and discuss the state of the art of biomarker use in ongoing Alzheimer's disease (AD) research. A review of 222 ongoing phase 1, 2, 3, and 4 protocols registered in the clinicaltrials.gov database was performed. All the trials (i) enrolling subjects with clinical disturbances and/or preclinical diagnoses falling within the AD continuum; and (ii) testing the efficacy and/or safety/tolerability of a therapeutic intervention, were analyzed. The use of biomarkers of amyloid deposition, tau pathology, and neurodegeneration among the eligibility criteria and/or study outcomes was assessed. Overall, 58.2% of ongoing interventional studies on AD adopt candidate biomarkers. They are mostly adopted by studies at the preliminary stages of the drug development process to explore the safety profile of novel therapies, and to provide evidence of target engagement and disease-modifying properties. The biologically supported selection of participants is mostly based on biomarkers of amyloid deposition, whereas the use of biomarkers as study outcomes mostly relies on markers of neurodegeneration. Biomarkers play an important role in the design and conduction of research protocols targeting AD. Nevertheless, their clinical validity, utility, and cost-effectiveness in the "real world" remain to be clarified

Amyotrophic Lateral Sclerosis and soccer: an internet survey of 29 Italian players

Objectives  Some epidemiological studies have shown a very high risk of  Amyotrophic Lateral Sclerosis (ALS) in Italian male soccer players. Subsequently, the sports newspapers and news agencies have spread the news of 51 male soccer players with reported ALS. Design  We searched for male Italian national soccer players quoted in at least two Internet web sites or in books of journalists from January 1, 1950 to July 31, 2016 with a reported diagnosis of ALS. Results. Thirty nine male soccer players with reported ALS were identified. These subjects were born from 1905 to 1973 (32 deceased 6 living and 1 unknown). In the group of 29 soccer players for which the information was available the mean age at diagnosis was 45.3± 12.2 years; the mean age at onset of symptoms was 46.4± 12.1 years; the mean age at death was 50.9± 12.3 years. An inverse statistically correlation between year of birth and age at onset of symptoms was observed, with a more younger age at onset of symptoms for soccer players born in the recent years (r =-0.65 p<0.01). Conclusions. The ALS Italian male soccer have a clear anticipation of the age of diagnosis respect to European ALS patients. The findings support the possible relation between the soccer and the occurrence of ALS. We believe that an increase in research activity is urgently needed in this field

The Italian national survey on coronavirus disease 2019 epidemic spread in nursing homes

Introduction: Residents in facilities such as nursing homes (NHs) are particularly vulnerable to Coronavirus disease 2019 (COVID-19). A national survey was carried out to collect information on the spreading and impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in nursing homes, and on how suspected and/or confirmed cases were managed. We carried out a survey between 25 March 2020 and 5 May 2020. Materials and methods: All Italian nursing homes either public or providing services both privately and within the NHS were included in the study. An on-line questionnaire was sent to 3292 nursing homes across all Italian regions. Nursing homes were also contacted by telephone to provide assistance in completing the questionnaire. Results: A total of 1356 nursing homes voluntarily participated to the survey, hosting a total of 100,806 residents. Overall, 9154 residents died due to any cause from February 1 to the time when the questionnaire was completed (from March 25 to May 5). Of these, 7.4% had COVID-19 and 33.8% had flu-like symptoms, corresponding to a cumulative incidence of 0.7 and 3.1, respectively. Lack of personnel, difficulty in transferring patients to hospital or other facility, isolating residents with COVID-19, number of beds and geographical area were the main factor positively associated to the presence of COVID-19 in nursing homes. Discussion: This survey showed the dissemination and impact of SARS-CoV-2 infection in Italian nursing homes and on how older and potentially chronically ill people residing in these long-term care facilities were managed

A Systematic Review of the Microbiome in Children With Neurodevelopmental Disorders

Background and Purpose: A relationship between gut microbiome and central nervous system (CNS), have been suggested. The human microbiome may have an influence on brain's development, thus implying that dysbiosis may contribute in the etiology and progression of some neurological/neuropsychiatric disorders. The objective of this systematic review was to identify evidence on the characterization and potential distinctive traits of the microbiome of children with neurodevelopmental disorders, as compared to healthy children.Methods: The review was performed following the methodology described in the Cochrane handbook for systematic reviews, and was reported based on the PRISMA statement for reporting systematic reviews and meta-analyses. All literature published up to April 2019 was retrieved searching the databases PubMed, ISI Web of Science and the Cochrane Database of Systematic Reviews. Only observational studies, published in English and reporting data on the characterization of the microbiome in humans aged 0-18 years with a neurodevelopmental disorder were included. Neurodevelopmental disorders were categorized according to the definition included in the Diagnostic and Statistical Manual of Mental Disorders, version 5 (DSM-5).Results: Bibliographic searches yielded 9,237 records. One study was identified through other data sources. A total of 16 studies were selected based on their relevance and pertinence to the topic of the review, and were then applied the predefined inclusion and exclusion criteria. A total of 10 case-control studies met the inclusion criteria, and were thus included in the qualitative analysis and applied the NOS score. Two studies reported data on the gut microbiome of children with ADHD, while 8 reported data on either the gut (n = 6) or the oral microbiome (n = 2) of children with ASD.Conclusions: All the 10 studies included in this review showed a high heterogeneity in terms of sample size, gender, clinical issues, and type of controls. This high heterogeneity, along with the small sample size of the included studies, strongly limited the external validity of results. The quality assessment performed using the NOS score showed an overall low to moderate methodological quality of the included studies. To better clarify the potential role of microbiome in patients with neurodevelopmental disorders, further high-quality observational (specifically cohort) studies are needed

[From mild cognitive impairment to dementia: what is the role of public health?]

Mild cognitive impairment (MCI) is a nosological entity proposed by Petersen in 1999 with the objective of identifying an early stage of dementia. The new diagnostic criteria for dementia, both those promoted by the International Working Group (IWG) and those defined by the National Institute of Aging (NIA), subsequently introduced a new model that starts with a preclinical phase, then proceeds with a prodromal phase, and ends with a phase of dementia. The condition known as subjective cognitive disorder (SCD) is included between the preclinic and the prodromal phases. Most clinicians improperly consider MCI and SCD as diseases, and not as risk factors for dementia. This ambiguous scenario requires the application of a public-health standard. A diagnosis of either SCD or MCI comes with several uncertainties, raising issues pertaining to both the research setting and clinical practice. A large proportion of subjects with either SCD or MCI will never progress to dementia, and part of them may even revert to a normal cognitive profile. Thus, communicating of these diagnoses to a subject has ethical implications that cannot be underestimated. The frequency of these diagnoses in general population is starting to show the characteristics of both the phenomena of over-diagnosis, and consequently over-treatment. Moreover, the new criteria require the use of biomarkers, that are not yet validated for the use in clinical practice. No population studies are currently available performed based on the new diagnostic criteria for dementia. This means that future estimates will probably be more than twice the current ones, and will include also subjects that will not progress to dementia. This undefined framework, thus, urges the implementation of public-health programs aimed at both the primary and secondary prevention of dementias. Moreover, clinical trials on drugs in MCI currently use endpoints based on non-validated biomarkers, thus raising the issue of the external validity. A public guideline would thus be crucial to support clinicians in identifying all the possible causes that can determine a cognitive decline people that are mainly elder, with multiple comorbidities, and taking multiple medications. Moreover, the widespread use of neuro-psychological assessment tools in current clinical practice requires an accurate validation of these instruments

Macrophages Transmit Human Immunodeficiency Virus Type 1 Products to CD4-Negative Cells: Involvement of Matrix Metalloproteinase 9▿

It was previously reported that human immunodeficiency virus type 1 (HIV-1) spreads in CD4 lymphocytes through cell-to-cell transmission. Here we report that HIV-1-infected macrophages, but not lymphocytes, transmit HIV-1 products to CD4-negative cells of either epithelial, neuronal, or endothelial origin in the absence of overt HIV-1 infection. This phenomenon was detectable as early as 1 h after the start of cocultivation and depended on cell-to-cell contact but not on the release of viral particles from donor cells. Transfer of HIV-1 products occurred upon their polarization and colocalization within zones of cell-to-cell contact similar to virological synapses. Neither HIV-1 Env nor Nef expression was required but, interestingly, we found that an HIV-1-dependent increase in matrix metalloproteinase 9 production from donor cells significantly contributed to the cell-to-cell transmission of the viral products. The macrophage-driven transfer of HIV-1 products to diverse CD4-negative cell types may have a significant role in AIDS pathogenesis