Precision Medicine in Alzheimer’s Disease: Investigating Comorbid Common Biological Substrates in the Rat Model of Amyloid Beta-Induced Toxicity

Alzheimer’s disease (AD), one of the most widespread neurodegenerative disorder, is a fatal global burden for the elder population. Although many efforts have been made, the search of a curative therapy is still ongoing. Individuating phenotypic traits that might help in investigating treatment response is of growing interest in AD research. AD is a complex pathology characterized by many comorbidities, such as depression and increased susceptibility to pain perception, leading to postulate that these conditions may rely on common biological substrates yet to be determined. In order to investigate those biological determinants to be associable with phenotypic traits, we used the rat model of amyloid beta-induced toxicity. This established model of early phase of AD is obtained by the intracerebroventricular injection of soluble amyloid beta1-42 (Aβ) peptide 7 days before performing experiments. In this model, we have previously reported increased immobility in the forced swimming test, reduced cortical serotonin levels and subtle alterations in the cognitive domain a depressive-like phenotype associated with subtle alteration in memory processes. In light of evaluating pain perception in this animal model, we performed two different behavioral tests commonly used, such as the paw pressure test and the cold plate test, to analyze mechanical hyperalgesia and thermal allodynia, respectively. Behavioural outcomes confirmed the memory impairment in the social recognition test and, compared to sham, Aβ-injected rats showed an increased selective susceptibility to mechanical but not to thermal stimulus. Behavioural data were then corroborated by neurochemical and biochemical biomarker analyses either at central or peripheral level. Data showed that the peptide injection evoked a significant increase in hypothalamic glutamate, kynurenine and dopamine content, while serotonin levels were reduced. Plasma Cystatin-C, a cysteine protease, was increased while serotonin and melatonin levels were decreased in Aβ-injected rats. Urinary levels paralleled plasma quantifications, indicating that Aβ-induced deficits in pain perception, mood and cognitive domain may also depend on these biomarkers. In conclusion, in the present study, we demonstrated that this animal model can mimic several comorbid conditions typical of the early phase of AD. Therefore, in the perspective of generating novel therapeutic strategies relevant to precision medicine in AD, this animal model and the biomarkers evaluated herein may represent an advantageous approach.

Autofluorescence Spectroscopy and Imaging II: A Special Issue Aimed to Promote Optically Based Studies on Biological Substrates

The Journal Molecules, in particular the Photochemistry Section, and the younger Journal Photochem are active in promoting the advances and practical applications based on the interaction of light with the various biological substrates from both animal and vegetal systems [...]

Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish

Orphan cytochrome P450 (CYP) enzymes are those for which biological substrates and function(s) are unknown. Cytochrome P450 20A1 (CYP20A1) is the last human orphan P450 enzyme, and orthologs occur as single genes in every vertebrate genome sequenced to date. The occurrence of high levels of CYP20A1 transcripts in human substantia nigra and hippocampus and abundant maternal transcripts in zebrafish eggs strongly suggest roles both in the brain and during early embryonic development. Patients with chromosome 2 microdeletions including CYP20A1 show hyperactivity and bouts of anxiety, among other conditions. Here, we created zebrafish cyp20a1 mutants using CRISPR/Cas9, providing vertebrate models with which to study the role of CYP20A1 in behavior and other neurodevelopmental functions. The homozygous cyp20a1 null mutants exhibited significant behavioral differences from wild-type zebrafish, both in larval and adult animals. Larval cyp20a1-/- mutants exhibited a strong increase in light-simulated movement (i.e., light–dark assay), which was interpreted as hyperactivity. Further, the larvae exhibited mild hypoactivity during the adaptation period of the optomotor assays. Adult cyp20a1 null fish showed a pronounced delay in adapting to new environments, which is consistent with an anxiety paradigm. Taken together with our earlier morpholino cyp20a1 knockdown results, the results described herein suggest that the orphan CYP20A1 has a neurophysiological role.

Why Does Music Evoke Strong Emotions?

Although much is known about the brain mechanisms underlying music perception and cognition, there is much work to be done in understanding aesthetic responses to music: Why does music make us feel the way we do? Why does it make us feel anything? In the article under discussion, the authors suggest that the brain’s own endogenous opioids mediate musical emotion, using the hypothesis of naltrexone-induced musical anhedonia. They conclude that endogenous opioids are critical to experiencing both positive and negative emotions in music and that music uses the same reward pathways as food, drugs, and sexual pleasure. Their findings add to the growing body of evidence for the evolutionary biological substrates of music.

Distributed Subnetworks of Depression Defined by Direct Intracranial Neurophysiology

Major depressive disorder is a common and disabling disorder with high rates of treatment resistance. Evidence suggests it is characterized by distributed network dysfunction that may be variable across patients, challenging the identification of quantitative biological substrates. We carried out this study to determine whether application of a novel computational approach to a large sample of high spatiotemporal resolution direct neural recordings in humans could unlock the functional organization and coordinated activity patterns of depression networks. This group level analysis of depression networks from heterogenous intracranial recordings was possible due to application of a correlational model-based method for inferring whole-brain neural activity. We then applied a network framework to discover brain dynamics across this model that could classify depression. We found a highly distributed pattern of neural activity and connectivity across cortical and subcortical structures that was present in the majority of depressed subjects. Furthermore, we found that this depression signature consisted of two subnetworks across individuals. The first was characterized by left temporal lobe hypoconnectivity and pathological beta activity. The second was characterized by a hypoactive, but hyperconnected left frontal cortex. These findings have applications toward personalization of therapy.

Method for Determining Regional Reference Values of Metal Content in Biological Substrates and Their Intake into the Body via Drinking Water

Natural and manmade flows of matter form complex metal associations in the body of residents living in certain territories, which leads to functional disorders in their bodies and the depletion of adaptive reserves. It is possible to assess the distribution of metals in the body only taking into account its biogeochemical localization. The question arises about the methodological approach to the determination of regional reference values of the concentrations of metals in biosubstrates of residents of different territories, to which this study was devoted. A designed and trained neural network was used, reflecting the relationship between the concentrations of metals in consumed drinking water and biosubstrates of the body, taking into account the physiological characteristics of the tested group of children and adolescents, based on the regional reference values obtained. Neural network regression methods allowed the calculation of nonlinear dependences of indicators of the state of the internal environment of an organism with external factors, and localized reference values determined in such calculations the indicators of the base state, being guided by the intensity of external factors, which should be assessed. The results of this study are intended for patient-oriented diagnosis and the treatment of eco-conditioned microelementosis in individual locations.

Intoxications by lead and its inorganic compounds

Lead belongs to the group of blood poisons that impair the synthesis of porphyrins and heme. Under industrial conditions, only chronic lead poisoning can develop. Lead belongs to the poisons that have the effect of material cumulation. The half-life of lead is 20 years. Once in the body, it is deposited in many organs in the form of the insoluble tribasic lead phosphates. A significant part of the lead is deposited in the trabeculae of the bones. Under the influence of provoking factors, an intensive lead release from the depot can be observed. In such cases, the amount of lead in the circulating blood increases sharply, and remission is replaced by an exacerbation. There is a wavy course of chronic lead intoxication. Lead and its inorganic compounds belong to the group of poisons that have a polytropic effect on the body, affecting many organs and systems. The blood system (anemia with specific characteristics) and the nervous system (polyneuropathy and encephalopathy) are primarily affected. A number of other organs and systems are also affected. The most severe specific syndrome of gastrointestinal tract damage is lead colic. Due to the impaired synthesis of porphyrins and heme in certain biological substrates of the body — in the blood, erythrocytes and urine, substances unused in the synthesis of heme are accumulated. They are markers of chronic intoxication caused by lead, in the presence of a relevant clinical picture. The diagnosis is based on data from a professional history, sanitary and hygienic characteristics of working conditions, clinical and objective characteristics of the disease and data from laboratory examination. The main thing is to stop contact with lead and remove it from the body. Antidotes for lead poisoning are chelators: tetacinum-calcium, pentacinum, D-penicillamine. In combination with technical and sanitary-hygienic measures to prevent chronic intoxication caused by lead, preliminary and periodic medical examinations of persons in contact with lead are of great importance.

Orphan cytochrome P450 20A1 CRISPR/Cas 9 mutants and neurobehavioral phenotypes in zebrafish

Orphan cytochrome P450 (CYP) enzymes are those for which biological substrates and function(s) are unknown. Cytochrome P450 20A1 (CYP20A1) is the last human orphan P450 enzyme, and orthologs occur as single genes in every vertebrate genome sequenced to date. The occurrence of high levels of CYP20A1 transcripts in human substantia nigra and hippocampus and abundant maternal transcripts in zebrafish eggs strongly suggest roles both in the brain and during early embryonic development. Patients with chromosome 2 microdeletions including CYP20A1 show hyperactivity and bouts of anxiety, among other conditions. Here, we created zebrafish CYP20A1 mutants using CRISPR/Cas9, providing vertebrate models with which to study the role of CYP20A1 in behavior and other neurodevelopmental functions. The homozygous cyp20a1 null mutants exhibited significant behavioral differences from wild-type zebrafish, both in larval and adult animals. Larval cyp20a1-/- mutants exhibited a strong increase in light-simulated movement (i.e., light-dark assay), which was interpreted as hyperactivity. Further, the larvae exhibited mild hypoactivity during the adaptation period of the optomotor assays. Adult cyp20a1 null fish showed a pronounced delay in adapting to new environments, which is consistent with an anxiety paradigm. Taken together with our earlier morpholino cyp20a1 knockdown results, the results described herein suggest that the orphan CYP20A1 has a neurophysiological role.

Maternal and neonatal canine cortisol measurement in multiple matrices during the perinatal period: A pilot study

Stress exposure during perinatal period may lead to maternal cortisol increase that negatively affects the offspring development. In recent years, the interest on non-invasive sampling methods to measure cortisol as a marker of stress is increasing in both humans and animals. Indeed, discomfort due to blood collection may compromise the diagnostic outcome, mainly in uncooperative patients. So far, some alternative matrices but not milk have been explored in adult dogs, while no data are available on the neonate and paediatric live pups. This study aimed to measure cortisol concentration in different biological substrates in both dams (blood, saliva, hair and milk) and pups (saliva and hair) at established times from proestrus up to two months after parturition. For this purpose, five female German shepherd bitches and their 22 pups were enrolled. Cortisol concentration was assessed using the enzyme immunoassay kit (Salivary Cortisol ELISA kit, Salimetrics) after matrices appropriate preparation if required. Cortisol was measurable in all the substrates, except some milk samples below the detection limit. Maternal cortisol concentrations differed among the matrices (P <0.0001) with the highest values recorded in plasma (median 0.596 μg/dL) compared to saliva (median 0.159 μg/dL), hair (median 0.083 μg/dL) and milk (median 0.045 μg/dL). Cortisol in dams did not vary within the same matrix over time. In pups, salivary (median 0.295 μg/dL) cortisol was always higher than hair (median 0.049 μg/dL; P <0.0001). At birth (P = 0.01) and two months later (P = 0.05), neonatal salivary cortisol was higher compared to other samplings. The present study demonstrates the suitability of these innovative substrates for cortisol measurement, suggesting them as potential diagnostic support in canine neonatology and welfare.