Cerebral blood flow and Aβ-amyloid estimates by WARM analysis of [¹¹C]PiB uptake distinguish among and between neurodegenerative disorders and aging

Background: We report results of the novel Washout Allometric Reference Method (WARM) that uses estimates of cerebral blood flow and amyloid load from the same [C]Pittsburgh Compound B ([C]PiB) retention maps in brain to distinguish between patients with different forms dementia, including Alzheimer's disease, and healthy volunteers. The method introduces two approaches to the identification of brain pathology related to amyloid accumulation, (1) a novel analysis of amyloid binding based on the late washout of the tracer from brain tissue, and (2) the simultaneous estimation of absolute cerebral blood flow indices (sCBF) from the early accumulation of the tracer in brain tissue. Objective: We tested the hypothesis that a change of cerebral blood flow is correlated with the degree of tracer [C]PiB retention, reflecting dendritic spine pathology and consequent inhibition of brain energy metabolism and reduction of blood flow by neurovascular coupling in neurodegenerative disorders, including Alzheimer's disease. Methods: Previously reported images of [C]PiB retention in brain of 29 subjects with cognitive impairment or dementia [16 Alzheimer's Disease (AD), eight subjects with dementia with Lewy bodies (DLB), five patients with frontotemporal lobar degeneration (FTLD), five patients with mild cognitive impairment, and 29 age-matched healthy control subjects (HC)], underwent analysis of PiB delivery and retention by means of WARM for quantitation of [C]PiB's binding potentials (BP) and correlated surrogate cerebral blood flow (sCBF) estimates, based on the [C]PiB images, compared to estimates by conventional Standard Uptake Value Ratio (SUVR) of [C]PiB retention with cerebellum gray matter as reference. Receiver Operating Characteristics (ROC) revealed the power of discrimination among estimates. Results: For AD, the discriminatory power of [C]PiB binding potential (BP) by WARM exceeded the power of SUVR that in turn exceeded the power of sCBF estimates. Differences of [C]PiB binding and sCBF measures between AD and HC both were highly significant (p < 0.001). For all the dementia groups as a whole, sCBF estimates revealed the greatest discrimination between the patient and HC groups. WARM resolves a major issue of amyloid load quantification with [C]PiB in human brain by determining absolute sCBF and amyloid load measures from the same images. The two parameter approach provides key discriminary information in AD for which [C]PiB traditionally is used, as well as for the distinct flow deficits in FTLD, and the marked parietal and occipital lobe flow deficits in DLB. Conclusion: We conclude that WARM yields estimates of two important variables that together discriminate among patients with dementia, including AD, and healthy volunteers, with ROC that are superior to conventional methods of analysis. The distinction between estimates of flow and amyloid load from the same dynamic emission tomograms provides valuable pathogenetic information

Molecular Insights Into Memory-Enhancing Metabolites of Nicotine in Brain: A Systematic Review

Background: The alleged procognitive effects of nicotine and its metabolites in brain are controversial.Objective: Here, we review the pharmacologically active metabolites of nicotine in brain and their effects on neuronal mechanisms involving two main cognitive domains, i.e., learning and memory.Methods: We searched Embase, Medline via PubMed, Scopus, and Web of Science databases for entries no later than May 2018, and restricted the search to articles about nicotine metabolites and cognitive behavior or cognitive mechanisms.Results: The initial search yielded 425 articles, of which 17 were eligible for inclusion after application of exclusion criteria. Of these, 13 were experimental, two were clinical, and two were conference papers.Conclusions: The results revealed three pharmacologically active biotransformations of nicotine in the brain, including cotinine, norcotinine, and nornicotine, among which cotinine and nornicotine both had a procognitive impact without adverse effects. The observed effect was significant only for cotinine

Four decades of mapping and quantifying neuroreceptors at work in vivo by positron emission tomography

Decryption of brain images is the basis for the necessary translation of the findings from imaging to information required to meet the demands of clinical intervention. Tools of brain imaging, therefore, must satisfy the conditions dictated by the needs for interpretation in terms of diagnosis and prognosis. In addition, the applications must serve as fundamental research tools that enable the understanding of new therapeutic drugs, including compounds as diverse as antipsychotics, antidepressants, anxiolytics, and drugs serving the relief of symptoms from neurochemical disorders as unrelated as multiple sclerosis, stroke, and dementia. Here we review and explain the kinetics of methods that enable researchers to describe the brain\u27s work and functions. We focus on methods invented by neurokineticists and expanded upon by practitioners during decades of experimental work and on the methods that are particularly useful to predict possible future approaches to the treatment of neurochemical disorders. We provide an overall description of the basic elements of kinetics and the underlying quantification methods, as well as the mathematics of modeling the recorded brain dynamics embedded in the images we obtai

Quantitative estimation of tissue blood flow rate

The rate of blood flow through a tissue (F) is a critical parameter for assessing the functional efficiency of a blood vessel network following angiogenesis. This chapter aims to provide the principles behind the estimation of F, how F relates to other commonly used measures of tissue perfusion, and a practical approach for estimating F in laboratory animals, using small readily diffusible and metabolically inert radio-tracers. The methods described require relatively nonspecialized equipment. However, the analytical descriptions apply equally to complementary techniques involving more sophisticated noninvasive imaging. Two techniques are described for the quantitative estimation of F based on measuring the rate of tissue uptake following intravenous administration of radioactive iodo-antipyrine (or other suitable tracer). The Tissue Equilibration Technique is the classical approach and the Indicator Fractionation Technique, which is simpler to perform, is a practical alternative in many cases. The experimental procedures and analytical methods for both techniques are given, as well as guidelines for choosing the most appropriate method

Nicotine Modulates Cognitive Function in D-Galactose-Induced Senescence in Mice

Here, we tested the claim that nicotine attenuates the signs of brain dysfunction in the model of brain aging induced by D-galactose (DGal) in mice. We administered nicotine at doses of 0.1, 0.5 and 1 mg/kg by the subcutaneous (s.c.) or at 0.1 mg/kg by the intranasal (i.n.) routes in mice that had received DGal at the dose of 500 mg/kg subcutaneous (s.c.) for 6 weeks. We assessed animal withdrawal signs as the number of presented somatic signs, thermal hyperalgesia, elevated plus maze (EPM) and open field tests. We evaluated spatial memory and recognition with Barnes maze and novel object recognition (NOR) tests. We tested brain tissue for reactive oxygen species (ROS), mitochondrial membrane potential, caspase-3, Bax, Bcl-2, cytochrome C, brain-derived neurotrophic factor and nerve growth factor levels. Nicotine administration in model groups (0.5 mg/kg s.c. and 0.1 mg/kg i.n. doses) significantly attenuated impairment of spatial and episodic memories in comparison to normal saline-received model group. These doses also reduced mito-oxidative damage as well as apoptosis and raised neurotrophic factors level in model groups in comparison to normal saline-received model group. The 1 mg/kg s.c. dose nicotine revealed withdrawal signs compared with the other nicotine-received groups. Nicotine at specific doses and routes has the potential to attenuate age-related cognitive impairment, mito-oxidative damage, and apoptosis. The doses raise neurotrophic factors without producing withdrawal signs

Molecular Insights Into Memory-Enhancing Metabolites of Nicotine in Brain:A Systematic Review

Background: The alleged procognitive effects of nicotine and its metabolites in brain are controversial. Objective: Here, we review the pharmacologically active metabolites of nicotine in brain and their effects on neuronal mechanisms involving two main cognitive domains, i.e., learning and memory. Methods: We searched Embase, Medline via PubMed, Scopus, and Web of Science databases for entries no later than May 2018, and restricted the search to articles about nicotine metabolites and cognitive behavior or cognitive mechanisms. Results: The initial search yielded 425 articles, of which 17 were eligible for inclusion after application of exclusion criteria. Of these, 13 were experimental, two were clinical, and two were conference papers. Conclusions: The results revealed three pharmacologically active biotransformations of nicotine in the brain, including cotinine, norcotinine, and nornicotine, among which cotinine and nornicotine both had a procognitive impact without adverse effects. The observed effect was significant only for cotinine.</p

Effect factors for marine invasion impacts on biodiversity

Purpose Marine vertebrate populations have halved in the past decades, and invasive species are a major driver for this loss. While many model the spread of invasive species, a model to assess impacts of marine invasions, after introduction, has hitherto been missing. We present the first regionalized effect factors for marine invasions. These factors gauge differences in biodiversity impacts after invasions, enabling life cycle impact assessments to highlight biodiversity impacts from invasive species. Methods Alien species are species that are introduced by humans to ecosystems where they are not native. We combine data from the IUCN red list and the MarINvaders database to identify the potentially disappeared fraction of native species within each marine coastal ecoregion after alien introduction. The effect factors indicate the biodiversity impact from invasions per alien introduction. However, the IUCN red list has a performance bias between taxonomic groups, and both the IUCN and the harmonized citizen science data from MarINvaders have a geographic observer’s bias. We address some of this bias by evaluating the number of threatened species per number of assessed species, as well as including machine-learning derived data for data deficient species. Results and discussion The resulting regional effect factors demonstrate high effects of invasions at high latitudes, which is in line with other findings. Our approach is founded on continuously growing citizen science data and so reflects the biases and uncertainties that follow with this uneven way of data sampling. On the other hand, the continuous data collection by citizen scientists will improve data coverage and thus improve the model. Vice versa, the model itself may be motivation for citizens scientists to collect more data. Conclusion The effect of marine invasions presented herein reflects current global information on the issue viewed in a perspective relevant for life cycle impact assessments. The developed effect factors can be used for further assessments that will aid decision-making for policies, industries, and consumers to work towards minimizing impacts of marine invasions and are developed to be compatible with different relevant fate factors.publishedVersio