Synthesis and in vitro evaluation of vanillin derivatives as multi-target therapeutics for the treatment of Alzheimer's disease.

A number of novel naphthalimido and phthalimido vanillin derivatives were synthesised, and evaluated as antioxidants and cholinesterase inhibitors in vitro. Antioxidant activity was assessed using DPPH, FRAP, and ORAC assays. All compounds demonstrated enhanced activity compared to the parent compound, vanillin. They also exhibited BuChE selectivity in Ellman's assay. A lead compound, 2a (2-(3-(bis(4-hydroxy-3-methoxybenzyl)amino)propyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione), was identified and displayed strong antioxidant activity (IC50 of 16.67 µM in the DPPH assay, a 25-fold increase in activity compared to vanillin in the FRAP assay, and 9.43 TE in the ORAC assay). Furthermore, 2a exhibited potent BuChE selectivity, with an IC50 of 0.27 µM which was around 53-fold greater than the corresponding AChE inhibitory activity. Molecular modelling studies showed that molecules with bulkier groups, as in 2a, exhibited better BuChE selectivity. This work provides a promising basis for the development of multi-target hybrid compounds based on vanillin as potential AD therapeutics.

Current and emerging therapeutic targets of alzheimer's disease for the design of multi-target directed ligands.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, and a major cause of death worldwide. The number of people suffering from this debilitating disorder is rising at an unprecedented rate, with a subsequent surge in healthcare costs. Only four drugs are clinically available for the treatment of AD symptoms, but they are not disease-modifying. Consequently, there is an urgent need for a cure. Although the cause of this debilitating condition remains poorly understood, it is believed that several factors may be involved in combination - including, health and lifestyle, environmental, and genetic factors. In recent years, a number of hallmarks of the disease have also been discovered, and it is believed that these factors may play an important role in the development of AD. Amyloid aggregation is one such factor which has been highly investigated, in addition to cholinesterase enzymes and tau aggregation. In the last decade, multi-target drugs have been increasingly investigated for their application to AD treatment. By combining two or more pharmacophores in a single compound, it is possible to synthesise a drug which can target several factors that are involved in AD development. This is a particularly attractive approach as it would avoid the use of combination therapies. As a result, it could reduce the burden on carers and families, and decrease healthcare and social care costs. Many active pharmacophores have been employed for the development of hybrid drugs, due to their abilities to inhibit the factors currently widely recognised to be involved in AD. These compounds have demonstrated promising results; however, research is still required to optimise the pharmacological profiles of the drugs, in addition to their potencies. Meanwhile, extensive research is continuously being performed into other potential targets for the treatment of AD. Based on the results obtained thus far, it is likely that multi-target compounds will continue to be increasingly studied in the future as potential treatments for AD.

Online tools for individuals with depression and neurologic conditions: A scoping review.

BACKGROUND: Patients with neurologic conditions commonly have depression. Online tools have the potential to improve outcomes in these patients in an efficient and accessible manner. We aimed to identify evidence-informed online tools for patients with comorbid neurologic conditions and depression. METHODS: A scoping review of online tools (free, publicly available, and not requiring a facilitator) for patients with depression and epilepsy, Parkinson disease (PD), multiple sclerosis (MS), traumatic brain injury (TBI), or migraine was conducted. MEDLINE, EMBASE, PsycINFO, Cochrane Database of Systematic Reviews, and Cochrane CENTRAL Register of Controlled Trials were searched from database inception to January 2017 for all 5 neurologic conditions. Gray literature using Google and Google Scholar as well as app stores for both Android and Apple devices were searched. Self-management or self-efficacy online tools were not included unless they were specifically targeted at depression and one of the neurologic conditions and met the other eligibility criteria. RESULTS: Only 4 online tools were identified. Of these 4 tools, 2 were web-based self-management programs for patients with migraine or MS and depression. The other 2 were mobile apps for patients with PD or TBI and depression. No online tools were found for epilepsy. CONCLUSIONS: There are limited depression tools for people with neurologic conditions that are evidence-informed, publicly available, and free. Future research should focus on the development of high-quality, evidence-based online tools targeted at neurologic patients.

Validating screening tools for depression in stroke and transient ischemic attack patients.

OBJECTIVE: The best screening questionnaires for detecting post-stroke depression have not been identified. We aimed to validate four commonly used depression screening tools in stroke and transient ischemic attack patients. METHODS: Consecutive stroke and transient ischemic attack patients visiting an outpatient stroke clinic in Calgary, Alberta (Canada) completed a demographic questionnaire and four depression screening tools: Patient Health Questionnaire (PHQ)-9, PHQ-2, Hospital Anxiety and Depression Scale (HADS-D), and Geriatric Depression Scale (GDS-15). Participants then completed the Structured Clinical Interview for DSM-IV (SCID), the gold-standard for diagnosing major depression. The questionnaires were validated against the SCID and sensitivity and specificity were calculated at various cut-points. Optimal cut-points for each questionnaire were determined using receiver-operating curve analyses. RESULTS: Among 122 participants, 59.5% were diagnosed with stroke and 40.5% with transient ischemic attack. The point prevalence of SCID-diagnosed current major depression was 9.8%. At the optimal cut-points, the sensitivity and specificity for each screening tool were as follows: PHQ-9 (sensitivity: 81.8%, specificity: 97.1%), PHQ-2 (sensitivity: 75.0%, specificity: 96.3%), HADS-D (sensitivity: 63.6%, specificity: 98.1%), and GDS-15 (sensitivity: 45.5%, specificity: 84.8%). Areas under the receiver operating characteristic curves were as follows: PHQ-9 86.6%, PHQ-2 86.7%, HADS-D 85.9%, and GDS-15 66.3%. CONCLUSIONS: The PHQ-2 and PHQ-9 are both suitable depression screening tools, taking less than 5 minutes to complete. The HADS-D does not appear to have any advantage over the PHQ-based scales, even though it was designed specifically for medically ill populations. The GDS-15 cannot be recommended for general use in a stroke clinic based on this study as it had worse discrimination due to low sensitivity.

The Prevalence and Incidence of Dementia: a Systematic Review and Meta-analysis.

UNLABELLED: Introduction Dementia is a common neurological condition affecting many older individuals that leads to a loss of independence, diminished quality of life, premature mortality, caregiver burden and high levels of healthcare utilization and cost. This is an updated systematic review and meta-analysis of the worldwide prevalence and incidence of dementia. METHODS: The MEDLINE and EMBASE databases were searched for relevant studies published between 2000 (1985 for Canadian papers) and July of 2012. Papers selected for full-text review were included in the systematic review if they provided an original population-based estimate for the incidence and/or prevalence of dementia. The reference lists of included articles were also searched for additional studies. Two individuals independently performed abstract and full-text review, data extraction, and quality assessment of the papers. Random-effects models and/or meta-regression were used to generate pooled estimates by age, sex, setting (i.e., community, institution, both), diagnostic criteria utilized, location (i.e., continent) and year of data collection. RESULTS: Of 16,066 abstracts screened, 707 articles were selected for full-text review. A total of 160 studies met the inclusion criteria. Among individuals 60 and over residing in the community, the pooled point and annual period prevalence estimates of dementia were 48.62 (CI95%: 41.98-56.32) and 69.07 (CI95%: 52.36-91.11) per 1000 persons, respectively. The respective pooled incidence rate (same age and setting) was 17.18 (CI95%: 13.90-21.23) per 1000 person-years, while the annual incidence proportion was 52.85 (CI95%: 33.08-84.42) per 1,000 persons. Increasing participant age was associated with a higher dementia prevalence and incidence. Annual period prevalence was higher in North America than in South America, Europe and Asia (in order of decreasing period prevalence) and higher in institutional compared to community and combined settings. Sex, diagnostic criteria (except for incidence proportion) and year of data collection were not associated with statistically significant different estimates of prevalence or incidence, though estimates were consistently higher for females than males. CONCLUSIONS: Dementia is a common neurological condition in older individuals. Significant gaps in knowledge about its epidemiology were identified, particularly with regard to the incidence of dementia in low- and middle-income countries. Accurate estimates of prevalence and incidence of dementia are needed to plan for the health and social services that will be required to deal with an aging population.