Blood-based biomarkers for Alzheimer's disease and related dementias: Keys to success and things to consider

During the last two decades, considerable progress has been made in the field of fluid and imaging biomarkers for neurodegenerative dementias. As a result, the most recent research and clinical guidelines (the National Institute on Aging and Alzheimer's Association, International Working Group 2, National Institute for Health and Care Excellence) incorporate cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers in the diagnostic criteria of dementia and mild cognitive impairment due to Alzheimer's disease (AD) [[1], [2], [3]]. However, as both CSF and amyloid PET examinations require expert knowledge and are of limited availability outside specialized memory clinics, there is no doubt that blood tests would be much easier to implement in clinical medicine and as screening tools when recruiting patients for clinical trials

Tau Imaging in Alzheimer's Disease Diagnosis and Clinical Trials

In vivo imaging of the tau protein has the potential to aid in quantitative diagnosis of Alzheimer's disease, corroborate or dispute the amyloid hypothesis, and demonstrate biomarker engagement in clinical drug trials. A host of tau positron emission tomography agents have been designed, validated, and tested in humans. Several agents have characteristics approaching the ideal imaging tracer with some limitations, primarily regarding off-target binding. Dozens of clinical trials evaluating imaging techniques and several pharmaceutical trials have begun to integrate tau imaging into their protocols

Suha travišča južne Evrope: sintaksonomija, gospodarjenje in ohranjenje

The Mediterranean area is a natural biodiversity hotspot that has also been influenced by humans for millennia. Especially the grasslands of Southern Europe have long been known for their diversity and beauty. However, several gaps remain in our knowledge about these grasslands, e.g. for some regions such as the southern Balkans, or taxonomic groups such as cryptogams. Here we introduce a Special Issue with contributions from the 9th European Dry Grassland Group meeting held in Prespa, Greece, 2012. The topic of this meeting was “Dry grasslands of Europe: grazing and ecosystem services” with special focus on Southern European regions. The Special Issue, apart from this Editorial, consists of eight contributions arranged according to the three major topics: syntaxonomy (5 articles), management (2) and conservation (1). The classification papers include descriptions of four new associations and four subassociations. Data about management practices are provided as well. We conclude that dry grassland vegetation in Southern Europe exhibits transitions between different higher syntaxa and thus requires further studies at broader scales to allow better understanding at the supranational scale.Mediteran je naravna vroča točka biodiverzitete, na katero je človek tisočletja močno vplival. Po svoji raznolikosti in lepoti so še posebej že dolgo znana travišča južne Evrope, vendar so v poznavanju teh travišč prisotne številne vrzeli na območju južnega Balkana ali posameznih taksonomskih skupin, kot so kriptogami. Predstavljamo posebno številko s prispevki z 9. srečanja Evropske skupine za suha travišča (European Dry Grassland Group), ki je bilo leta 2012 v mestu Prespa (Grčija). Tema srečanja je bila “Suha travišča Evrope: paša in ekosistemske storitve” s posebnim poudarkom na območjih južne Evrope. Posebno številko poleg tega uvodnika sestavlja osem prispevkov, ki smo jih uredili v tri glavne teme: sintaksonomijo (5 člankov), gospodarjenje (2) in ohranjanje travišč (1). Članki o klasifikaciji vsebujejo opise štirih novih asociacij in štirih subasociacij. Prav tako vsebujejo podatke o načinu gospodarjenja. Zaključimo lahko, da kaže vegetacija suhih travišč v južni Evropi prehod med različnimi višjimi sintaksoni in zato so potrebne nadaljnje raziskave v večjem merilu, ki bodo omogočile boljše razumevanje v nadnacionalnem merilu

Possible role of 18-kDa translocator protein (TSPO) in etifoxine-induced reduction of direct twitch responses in isolated rat nerve-skeletal muscle preparations

Purpose: To determine the effects of etifoxine on directly-elicited twitch tension of isolated rat nerveskeletal muscle preparations and to propose a possible explanation of the mechanism of the observed effect.Methods: Striated muscles contractile activity was elicited by electrical field stimulation. The effects of etifoxine and nifedipine on direct single twitch response were studied.Results: The results demonstrate that the effect of etifoxine on skeletal muscle depends on the concentrations: low concentrations (10-8 М and 10-7 М) have little effect on twitch tension, whereas higher concentrations (10-6 М and 10-5 М) induced a significant decrease in the direct single twitch response in comparison to controls. The mean IC50 (reduction of directly-elicited twitch tension) of etifoxine was 0.85 x 10-6 M. The selective L-type calcium channel blocker nifedipine (10-5 М) induced a greater decrease in the muscle force than 10-6 М etifoxine. The different abilities of etifoxine and nifedipine to reduce direct single twitch response may be related to their distinct mechanisms of action. The observed effect of etifoxine could be more complex. Probably etifoxine acts as a non-selective agent not only on L-type calcium channels Cav1.1 localized in sarcolemma but also on 18-kDa translocator protein (TSPO) in skeletal muscle.Conclusion: Etifoxine-induced reduction of direct twitch responses could be attributed to an effect on TSPO and Cav1.1. Knowledge of the effects of TSPO ligands on the contraction of skeletal muscle might explain the role of TSPO in muscle contractility.Keywords: Etifoxine, TSPO, Calcium channels, Direct single twitch response, Striated muscl

Denatonium benzoate decreases the effect of histamine in vitro and in rats

Purpose: To evaluate the effect of denatonium benzoate (DB) in histamine-induced model of inflammation and the effect of the selective H1 receptor agonist (2-(2-Pyridyl) ethylamine) on rat gastric smooth muscle strips pretreated with DB.Methods: The anti-inflammatory effect of DB was evaluated in vivo on histamine-induced rat paw edema. In vitro studies on spontaneous muscle contraction were performed on smooth muscle strips isolated from rat gastric corpus.Results: The results showed a well-defined anti-inflammatory effect of DB (15 mg/kg) during the early stage of rat paw edema at the 15th (p < 0.001), 30th (p < 0.01) and 60th min (p < 0.001) compared to control. In vitro experiments indicated reduced spontaneous contractile activity of smooth muscle strips to H1 receptor agonist in the presence of DB (0.5 μM). The vascular effects of histamine are mediated by H1 receptors. Substances, which reduce the effect of histamine on the H1 receptors could influence the early stage of histamine-induced inflammation.Conclusion: The results show that the anti-inflammatory activity of DB probably is related to its antagonistic activity on histamine H1 receptors. The results would contribute to the search for new antiinflammatory drugs. Keywords: Denatonium benzoate, Inflammation, Histamine, Muscle contractio

FLORA, MYCOTA AND VEGETATION OF KUPENA RESERVE (RODOPI MOUNTAINS, BULGARIA)

The paper represents results from recent complex studies of flora, mycota and vegetation within the Kupena Reserve (Rodopi Mts, Bulgaria). Twenty three species, referred to 2 divisions, 4 classes and 16 families are recorded for the bryoflora. The vascular flora is presented by 368 species from 57 families, 121 of which are considered as medicinal plants. Eighty seven species of larger ascomycetes and basidiomycetes are found and reported for first time in the reserve. Four of them are of a high conservation value. The vegetation cover is consisted of mixed and monodominant deciduous and coniferous forests, as well as of mire, riverbank and mesic grasslands. Thirteen types of habitats according to the Habitats Directive classification have been recorded within the reserve

The Functional Ability of MCI and Alzheimer’s Patients Predicts Caregiver Burden

Research shows that caregivers of dementia patients experience burden and psychological distress, but it is unclear whether or not caregivers of individuals with cognitive impairments that do not meet a diagnosis for dementia also experience similar burdens and psychological problems. Sixty patients and their caregivers participated in this study designed to examine caregiver burden. The patients completed activities-of-daily-living tasks and several neuropsychological tests assessing memory, abstract reasoning, and language. Caregivers completed self-report measures assessing caregiver burden and psychological distress. Results revealed that the caregivers of patients with mild Alzheimer’s disease (mAD) reported greater physical burden and feelings of missing out on life compared to individuals with mild cognitive impairment (MCI) caregivers. The mAD caregivers indicated greater depression and anxiety relative to MCI caregivers. Stepwise regression found that patient neuropsychological scores were worse predictors of caregiver burden than patients’ daily functioning. The conclusions of this study suggest that (1) caregivers of mAD are likely to experience more severe types of burden and psychological distress relative to caregivers of MCI patients, and that (2) patients’ daily functional abilities better predict caregivers’ burden and psychological distress than patients’ neuropsychological functioning. Study findings suggest that caregivers of those in the early stages of dementia, even in persons not yet meeting a diagnosis, experience psychological symptoms and burden, and that these caregivers’ experiences can be best predicted by the patients daily functional ability than by patients’ neuropsychological test scores

Carbopol hydrogel/sorbitan monostearate-almond oil based organogel biphasic formulations: Preparation and characterization of the bigels

Purpose: To obtain and evaluate carbopol hydrogel/sorbitan monostearate-almond oil-based organogel biphasic formulations (bigels) as a semi-solid vehicle for medicated topical applications.Methods: Bigel formulations were obtained under mild conditions at a hydrogel/organogel ratio of 80/20, 70/30, and 60/40 (w/w). Their stability, viscosity, spreadability, microarchitecture, and acute skin toxicity were evaluated.Results: Two formulations, prepared at ratios of 80/20 and 70/30, were stable based on intermediate stability testing, and had a similar viscosity and spreadability (38.0 ± 1.0 mm and 37.3 ± 0.6 mm, p > 0.05, respectively). Both of these formulations had a bimodal droplet size distribution and very similar values for the droplet mean diameter (0.33 ± 0.05 μm and 2.35 ± 0.44; and 0.34 ± 0.04 μm and 2.59 ± 0.21 μm). The formulation obtained at a ratio of 60/40 was unstable during storage. The in vivo results did not reveal any signs of skin toxicity.Conclusion: Considering their beneficial properties, the developed bigels are a potential semi-solid vehicle for topical application and exhibit a moisturizing effect.Keywords: Almond oil, Bigels, Carbopol hydrogel, Moisturizing effect, Organogel, Sorbitan monostearat

Association of Hypercholesterolemia with Alzheimer’s Disease Pathology and Cerebral Amyloid Angiopathy

Background: Animal studies have shown that diet-induced hypercholesterolemia (HC) increases amyloid-β (Aβ) accumulation and accelerates Alzheimer’s disease (AD) pathology. However, the association of HC with AD in human studies has not been consistently established. Objective: We aimed to investigate the relationship between HC and risk of AD neuropathology in a large national sample with autopsies. Methods: This study used neuropathological and clinical data from 3,508 subjects from the National Alzheimer’s Coordinating Center (NACC) who underwent autopsies from 2005 to 2017. Demographic and clinical characteristics, as well as neuropathological outcomes were compared between subjects with and without HC. Associations between HC and AD neuropathology were examined by multivariate ordinal logistic regressions adjusting for potential confounders. Results: HC was not associated with any AD neuropathology in a model only adjusting for demographic variables. However, HC was significantly associated with higher CERAD neuritic and diffuse plaque burden, higher Braak stage, and more severe cerebral amyloid angiopathy when analyzed in a multivariate model controlling for comorbidities. Additional adjusting for cerebrovascular conditions did not diminish these associations. The association between HC and increased risk of neuritic plaques weakened but remained significant even after controlling for ApoE genotype. Conclusion: This study suggested that HC was associated with increased severity of AD pathology, which could only be partially accounted for by ApoE genotype. The associations were not mediated by cerebrovascular conditions

Association of brain amyloidosis with the incidence and frequency of neuropsychiatric symptoms in ADNI: a multisite observational cohort study

Objective To investigate the relationship between amyloid burden and frequency of existing and incidence of new neuropsychiatric symptoms (NPS) in elderly with and without cognitive decline. Methods 275 cognitively normal controls (NC), 100 subjective memory complaint (SMC), 559 mild cognitive impairment (MCI) and 143 Alzheimer’s disease dementia subjects from the Alzheimer’s Disease Neuroimaging Initiative received (18F)-florbetapir positron emission tomography (PET) scans. Yearly neuropsychiatric inventory (Neuropsychiatric Inventory (NPI)/NPI-Questionnaire) data were collected from the study partners at each visit. Mean standard uptake volume ratios (SUVR) normalised to whole cerebellum were obtained. Positive amyloid PET scan was defined as mean SUVR ≥1.17. Fisher’s exact test was used to compare frequency and incidence between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate of neuropsychiatric symptoms (NPS) between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate hazard ratios for developing the most common NPS by amyloid status. Results No differences in NPS frequency were seen between amyloid positive and amyloid negative NC, SMC, MCI or dementia groups. MCI subjects with amyloid pathology however tended to have greater frequency x severity (FxS) of anxiety, hallucinations, delusions, apathy, disinhibition, irritability, aberrant motor behavior, and appetite, but not agitation, depression, night-time disturbances, or elation. MCI subjects with amyloid pathology were at greater risk for developing apathy, anxiety and agitation over time. Baseline presence of agitation and apathy and new onset agitation, irritability and apathy predicted faster conversion to dementia among MCI subjects. Conclusions Amyloid pathology is associated with greater rate of development of new NPS in MCI. Anxiety and delusions are significant predictors of amyloid pathology. Agitation, irritability and apathy are significant predictors for conversion from MCI to dementia