Correction: The Role of the Mammalian DNA End-processing Enzyme Polynucleotide Kinase 3'-Phosphatase in Spinocerebellar Ataxia Type 3 Pathogenesis.

[This corrects the article DOI: 10.1371/journal.pgen.1004749.].

Do physical fitness and cognitive function mediate the relationship between basic activities of daily living and quality of life in older adults with dementia?

PURPOSE: Independence in activities of daily living (ADLs) is associated with quality of life (QoL) in individuals with dementia. However, the contribution of physical and cognitive functions to this relationship needs further examination. This study aims to examine the mediating effect of physical fitness and cognitive function in the relationship between independence in basic ADLs and QoL among older adults with dementia. METHODS: This cross-sectional study included 107 older adults with dementia (74.8% women; age 78.21 ± 7.70 years). Independence in basic ADL and QoL were evaluated using the Barthel Index (BI) and QoL- Alzheimer's Disease Scale, respectively. The Alzheimer's Disease Assessment Scale-Cognitive Subscale and the Mini-Mental State Examination were applied to assess cognitive function. Physical fitness was evaluated using the 30-s chair stand, 2-min step and the Timed-Up and Go tests. A structural equation modelling (SEM) with bootstrapping estimation was conducted to determine the relationship between all variables. RESULTS: Independence in basic ADL positively affected QoL and this association was mediated by physical fitness (ß = 0.242, p = 0.011). No statistically significant results were observed when testing cognitive function as a mediator between BI and QoL (ß = 0.009, p = 0.345). CONCLUSIONS: Physical fitness (i.e., lower body strength, aerobic capacity, and mobility) plays a role in the relationship between basic ADL independence and QoL of older adults with dementia, reinforcing the need to improve and monitor these parameters throughout the disease progression. Future longitudinal studies should explore the temporal relationship between physical and cognitive function and its contribution to basic ADL independence and QoL.

The MEDITAGING study: protocol of a two-armed randomized controlled study to compare the effects of the mindfulness-based stress reduction program against a health promotion program in older migrants in Luxembourg.

BACKGROUND: Migration is a phenomenon worldwide, with older migrants, particularly those with fewer socioeconomic resources, having an increased risk of developing adverse cognitive and health outcomes and social isolation. Therefore, it is of utmost importance to validate interventions that promote healthy aging in this population. Previous studies have shown a positive impact of mindfulness based-stress reduction (MBSR) on outcomes such as cognition and sleep. However, only a few studies verified its potential in older adults, especially with vulnerable populations such as migrants. This article presents the protocol of the MEDITAGING study, which is the first to investigate the MBSR effects in migrants aged ≥55 in comparison to a health promotion program. METHODS: MEDITAGING is a two-arm randomized, double-blinded, controlled study, which will include older Portuguese-speaking migrants (n = 90). Participants are randomized to the MBSR or a health promotion program. Both interventions are conducted in groups over a total of 8 weeks, incorporating weekly meetings, an additional 4-hour class, and extra at-home tasks. The health promotion program has the same structure as the MBSR but comprises different activities related to dementia prevention, healthy habits, cognitive stimulation, sleeping, nutrition, watercolor painting, and physical activity. The assessment of executive functioning, physiological stress measures, self-reported questionnaires, and qualitative interviews are conducted at baseline, after 8 weeks (post-intervention), and at a follow-up session (from one to 3 months thereafter). Analyzes will be conducted using a modified intention-to-treat approach (all participants with at least 3 days of participation in the group-sessions and one post-intervention observation). DISCUSSION: This study will test effects of a mindfulness-based intervention against an active control condition in older adult migrants, which few studies have addressed. TRIAL REGISTRATION: ClinicalTrials.gov NCT05615337 (date of registration: 27 September 2022; date of record verification: 14 November 2022).

Neuroprotective Effects of Creatine in the CMVMJD135 Mouse Model of Spinocerebellar Ataxia Type 3.

BACKGROUND AND OBJECTIVE: Mitochondrial dysfunction has been implicated in several neurodegenerative diseases. Creatine administration increases concentration of the energy buffer phosphocreatine, exerting protective effects in the brain. We evaluate whether a creatine-enriched diet would be beneficial for a mouse model of spinocerebellar ataxia type 3, a genetically defined neurodegenerative disease for which no treatment is available. METHODS: We performed 2 independent preclinical trials using the CMVMJD135 mouse model (treating 2 groups of animals with different disease severity) and wild-type mice, to which 2% creatine was provided for 19 (preclinical trial 1) or 29 (preclinical trial 2) weeks, starting at a presymptomatic age. Motor behavior was evaluated at several time points from 5 to 34 weeks of age, and neuropathological studies were performed at the end of each trial. RESULTS: Creatine supplementation led to an overall improvement in the motor phenotype of CMVMJD135 mice in both trials, rescuing motor balance and coordination and also restored brain weight, mitigated astrogliosis, and preserved Calbindin-positive cells in the cerebellum. Moreover, a reduction of mutant ataxin-3 aggregates occurred despite maintained steady-state levels of the protein and the absence of autophagy activation. Creatine treatment also restored the expression of the mitochondrial mass marker Porin and reduced the expression of antioxidant enzymes Heme oxygenase 1 (HO1) and NAD(P)H Quinone Dehydrogenase 1 (NQO1), suggesting a beneficial effect at the level of mitochondria and oxidative stress. CONCLUSIONS: Creatine slows disease progression and improves motor dysfunction as well as ameliorates neuropathology of the CMVMJD135 animals, supporting this as a useful strategy to slow the progression of spinocerebellar ataxia type 3. © 2018 International Parkinson and Movement Disorder Society.

Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an untreatable autosomal dominant neurodegenerative disease, and the most common such inherited ataxia worldwide. The mutation in SCA3 is the expansion of a polymorphic CAG tri-nucleotide repeat sequence in the C-terminal coding region of the ATXN3 gene at chromosomal locus 14q32.1. The mutant ATXN3 protein encoding expanded glutamine (polyQ) sequences interacts with multiple proteins in vivo, and is deposited as aggregates in the SCA3 brain. A large body of literature suggests that the loss of function of the native ATNX3-interacting proteins that are deposited in the polyQ aggregates contributes to cellular toxicity, systemic neurodegeneration and the pathogenic mechanism in SCA3. Nonetheless, a significant understanding of the disease etiology of SCA3, the molecular mechanism by which the polyQ expansions in the mutant ATXN3 induce neurodegeneration in SCA3 has remained elusive. In the present study, we show that the essential DNA strand break repair enzyme PNKP (polynucleotide kinase 3'-phosphatase) interacts with, and is inactivated by, the mutant ATXN3, resulting in inefficient DNA repair, persistent accumulation of DNA damage/strand breaks, and subsequent chronic activation of the DNA damage-response ataxia telangiectasia-mutated (ATM) signaling pathway in SCA3. We report that persistent accumulation of DNA damage/strand breaks and chronic activation of the serine/threonine kinase ATM and the downstream p53 and protein kinase C-δ pro-apoptotic pathways trigger neuronal dysfunction and eventually neuronal death in SCA3. Either PNKP overexpression or pharmacological inhibition of ATM dramatically blocked mutant ATXN3-mediated cell death. Discovery of the mechanism by which mutant ATXN3 induces DNA damage and amplifies the pro-death signaling pathways provides a molecular basis for neurodegeneration due to PNKP inactivation in SCA3, and for the first time offers a possible approach to treatment.

The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3'-phosphatase in spinocerebellar ataxia type 3 pathogenesis.

DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3'-P and 5'-OH, are processed by mammalian polynucleotide kinase 3'-phosphatase (PNKP), a bifunctional enzyme with 3'-phosphatase and 5'-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14-41 to 55-82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP's 3' phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3'-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients' brain. Finally, long amplicon quantitative PCR analysis of human MJD patients' brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD.

Dominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells.

The physiological function of Ataxin-3 (ATXN3), a deubiquitylase (DUB) involved in Machado-Joseph Disease (MJD), remains elusive. In this study, we demonstrate that ATXN3 is required for neuronal differentiation and for normal cell morphology, cytoskeletal organization, proliferation and survival of SH-SY5Y and PC12 cells. This cellular phenotype is associated with increased proteasomal degradation of α5 integrin subunit (ITGA5) and reduced activation of integrin signalling and is rescued by ITGA5 overexpression. Interestingly, silencing of ATXN3, overexpression of mutant versions of ATXN3 lacking catalytic activity or bearing an expanded polyglutamine (polyQ) tract led to partially overlapping phenotypes. In vivo analysis showed that both Atxn3 knockout and MJD transgenic mice had decreased levels of ITGA5 in the brain. Furthermore, abnormal morphology and reduced branching were observed both in cultured neurons expressing shRNA for ATXN3 and in those obtained from MJD mice. Our results show that ATXN3 rescues ITGA5 from proteasomal degradation in neurons and that polyQ expansion causes a partial loss of this cellular function, resulting in reduced integrin signalling and neuronal cytoskeleton modifications, which may be contributing to neurodegeneration.

Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease.

Polyglutamine diseases are a class of dominantly inherited neurodegenerative disorders for which there is no effective treatment. Here we provide evidence that activation of serotonergic signalling is beneficial in animal models of Machado-Joseph disease. We identified citalopram, a selective serotonin reuptake inhibitor, in a small molecule screen of FDA-approved drugs that rescued neuronal dysfunction and reduced aggregation using a Caenorhabditis elegans model of mutant ataxin 3-induced neurotoxicity. MOD-5, the C. elegans orthologue of the serotonin transporter and cellular target of citalopram, and the serotonin receptors SER-1 and SER-4 were strong genetic modifiers of ataxin 3 neurotoxicity and necessary for therapeutic efficacy. Moreover, chronic treatment of CMVMJD135 mice with citalopram significantly reduced ataxin 3 neuronal inclusions and astrogliosis, rescued diminished body weight and strikingly ameliorated motor symptoms. These results suggest that small molecule modulation of serotonergic signalling represents a promising therapeutic target for Machado-Joseph disease.

Lithium chloride therapy fails to improve motor function in a transgenic mouse model of Machado-Joseph disease.

The accumulation of misfolded proteins in neurons, leading to the formation of cytoplasmic and nuclear aggregates, is a common theme in age-related neurodegenerative diseases, possibly due to disturbances of the proteostasis and insufficient activity of cellular protein clearance pathways. Lithium is a well-known autophagy inducer that exerts neuroprotective effects in different conditions and has been proposed as a promising therapeutic agent for several neurodegenerative diseases. We tested the efficacy of chronic lithium (10.4 mg/kg) treatment in a transgenic mouse model of Machado-Joseph disease, an inherited neurodegenerative disease, caused by an expansion of a polyglutamine tract within the protein ataxin-3. A battery of behavioral tests was used to assess disease progression. In spite of activating autophagy, as suggested by the increased levels of Beclin-1, Atg7, and LC3-II, and a reduction in the p62 protein levels, lithium administration showed no overall beneficial effects in this model concerning motor performance, showing a positive impact only in the reduction of tremors at 24 weeks of age. Our results do not support lithium chronic treatment as a promising strategy for the treatment of Machado-Joseph disease (MJD).

Feasibility and Effectiveness of a 12-Week Concurrent Exercise Training on Physical Performance, Muscular Strength, and Myokines in Frail Individuals Living in Nursing Homes: A Cluster Randomized Crossover Trial.

OBJECTIVE: To examine the feasibility and effects of a 12-week exercise intervention on physical performance, muscular strength, and circulating myokines in frail individuals living in nursing homes. DESIGN: A cluster randomized, 2-period, 2-intervention crossover trial. SETTING AND PARTICIPANTS: Frail residents of 9 nursing homes were randomly assigned to either 12 weeks of concurrent exercise training (n = 5, 29 participants) or usual care (n = 4, 17 participants). The concurrent exercise training consisted of resistance and aerobic exercises (3 days/week). The usual care consisted of everyday routine and standard care. After a 4-week washout period, participants crossed to the other intervention. METHODS: The feasibility outcomes included recruitment rate, dropout rate and reasons, harms during the trial, adherence to exercise, and implementation cost. The primary endpoint was the change in physical performance measured by the Short Physical Performance Battery (SPPB). The secondary endpoints were changes in muscular strength (eg, handgrip strength, isokinetic knee extension, and flexion strength) and serum myokines concentration (myostatin and decorin). RESULTS: From the 46 participants enrolled (aged 70-99 years, 67.4% female), 34 completed the trial (26.1% dropout rate), the median adherence was 93.75%, and no adverse events occurred during the exercise sessions. The concurrent exercise training provided significant benefits over usual care on SPPB (B = 2.18; 95% CI, 1.35-3.00; P < .001), handgrip strength (B = 2.15; 95% CI, 1.00-3.30; P < .001), myostatin concentrations (B = -7.07; 95% CI, -13.48 to -0.66; P = .031) and myostatin-decorin ratio (B = -95.54; 95% CI, -158.30 to -32.78, P = .004). No significant between-group differences were found for the remaining secondary endpoints. CONCLUSIONS AND IMPLICATIONS: This concurrent exercise training is feasible, well-tolerated, and effective in improving physical performance, handgrip strength, myostatin, and myostatin-decorin ratio concentrations in frail older adults residing in nursing homes. These data reinforce the relevance of integrating exercise interventions in long-term care settings.

Inflammatory biomarkers and perinatal depression: A systematic review.

BACKGROUND: Approximately 10 to 20% of pregnant women worldwide experience perinatal depression (PND), a depressive episode with onset during pregnancy or after childbirth. We performed a systematic review to identify, summarize and discuss studies on inflammatory biomarkers described in relation to PND. METHOD: Inclusion criteria defined the selection of observational studies written in English, French, Spanish or Portuguese, that evaluate analytical levels of inflammatory molecules (protein levels) in biological fluids in women, with a diagnosis of depression using ICD/DSM diagnostic criteria or depressive symptoms assessed by standardized psychometric instruments, during pregnancy and/or postpartum. Case reports, experimental studies, reviews, qualitative analysis, meta-analysis, gray literature or replicated data were excluded. Three electronic databases were used for search (Pubmed, Web of Science and PsychInfo) and quality assessment of selected studies were performed using the Newcastle-Ottawa Scale. Data extraction included study design; number of subjects; obstetric information; tools and timepoints of depression and inflammatory markers assessment. RESULTS: 56 studies (sample size for cross-sectional and case-control studies ranging from 10 to 469; sample size for longitudinal studies ranging from 26 to 467), where the major aim was to analyze the association between depression and inflammatory biomarkers during pregnancy and postpartum period were included in this systematic review. Overall, the findings of our systematic review lend support to the hypothesis that several inflammatory markers may be associated with peripartum depressive symptoms. The associations were somewhat different looking at pregnancy compared to the delivery time-point and postpartum, and mainly referred to increased levels of IL-6, IL-8, CRP and TNF-α among depressed. DISCUSSION: In summary, our systematic review findings provide evidence supporting the hypothesis that several inflammatory markers may correlate with peripartum depressive symptoms. However, our work also highlighted notable differences in the timing of biological sampling for inflammatory markers and in the methodologies used to assess depression during the perinatal period. Additionally, variations were observed in how inflammatory biomarkers and depression were approached, including their classification as exposure or outcome variables, and the timing of assessments. It is essential for future research to investigate the influence of biological fluids and the timing of assessments for both inflammatory biomarkers and depression to gain a deeper understanding of their association. This comprehensive exploration is pivotal for elucidating the intricate relationship between inflammation and perinatal depression.

Patterns of mitochondrial DNA damage in blood and brain tissues of a transgenic mouse model of Machado-Joseph disease.

BACKGROUND: Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia caused by a CAG tract expansions in the ATXN3 gene. Patterns of mitochondrial damage associated with pathological findings of brain tissues could provide molecular biomarkers of this disorder. OBJECTIVE: The potential of mitochondrial DNA (mtDNA) damage as a biomarker of MJD progression was investigated using a transgenic mouse model. METHODS: DNA was obtained from affected (pontine nuclei) and nonaffected tissues (hippocampus and blood) of transgenic animals of three distinct age groups: 8 weeks, before onset of the phenotype; 16 weeks, at onset, and 24 weeks, at well-established phenotype. Wild-type littermate mice, serving as controls, were analyzed for the same tissues and age groups. mtDNA damage was studied by fluorescence-based quantitative PCR in 84 transgenic and 93 wild-type samples. RESULTS: A clear pattern of decrease in mtDNA copy number with age and accumulation of 3,867-bp deletions at the initial stages (both being more pronounced in transgenic mice) was observed. Pontine nuclei, the affected tissue in transgenic mice, displayed 1.5 times less copies of mtDNA than nonaffected brain tissue hippocampus (odds ratio = 1.21). Pontine nuclei displayed the highest percentage of mtDNA deletions (6.05% more in transgenic mice). CONCLUSION: These results suggest that mtDNA damage is related to the initiation of the phenotype in transgenic mice; mtDNA 3,867-bp deletions may be a biomarker of the initial stages of the disease.

Non-pharmacological treatment-related changes of molecular biomarkers in major depressive disorder: A systematic review and meta-analysis.

Background: Major depressive disorder (MDD) is a serious mood disorder and leading cause of disability. Despite treatment advances, approximately 30% of individuals with MDD do not achieve adequate clinical response. Better understanding the biological mechanism(s) underlying clinical response to specific psychopharmacological interventions may help fine tune treatments in order to further modulate their underlying mechanisms of action. However, little is known regarding the effect of non-pharmacological treatments (NPTs) on candidate molecular biomarker levels in MDD. This review aims to identify molecular biomarkers that may elucidate NPT response for MDD. Methods: We performed a systematic review and a multilevel linear mixed-effects meta-analyses, and a meta-regression. Searches were performed in PubMed, Scopus, and PsycINFO in October 2020 and July 2021. Results: From 1387 retrieved articles, 17 and six studies were included in the systematic review and meta-analyses, respectively. Although there was little consensus associating molecular biomarker levels with symptomology and/or treatment response, brain metabolites accessed via molecular biomarker-focused neuroimaging techniques may provide promising information on whether an individual with MDD would respond positively to NPTs. Furthermore, non-invasive brain stimulation interventions significantly increased the expression of neurotrophic factors (NTFs) compared to sham/placebo, regardless of add-on pharmacological treatment. Conclusions: NTFs are candidate biomarkers to fine-tune NIBS for MDD treatment.

Processing speed mediates the association between physical activity and executive functioning in elderly adults.

Advanced aging is associated with cognitive decline. To decrease the healthcare system and socio-economic burdens as well as to promote better quality of life, is important to uncover the factors that may be related to the delay of cognitive impairments in older adults. This study investigated the relationship between physical activity levels, sedentary behavior and cardiorespiratory fitness with cognitive functioning in healthy older adults. Furthermore, it examined the mediating role of processing speed on the association between physical activity and executive functions and long-term memory. Thirty-two individuals aged between 63 and 77 years (M = 68.16, SD = 3.73) underwent measurements of maximal oxygen uptake (VO2peak), 1-week of PA accelerometer measurement and a comprehensive cognitive assessment. Significant associations were observed between MVPA and cognitive processing speed. Equally, a significant positive indirect effect of MVPA on executive functioning and long-term memory was mediated by processing speed. Also, MVPA levels differentiated cognitive functioning in older adults - the physical active group outperformed the physical inactive group in processing speed, executive functions, and language abilities. Our results contribute to the literature on the MVPA levels as an important tool to promote healthier cognitive aging.

Corrigendum: Processing speed mediates the association between physical activity and executive functioning in elderly adults.

[This corrects the article DOI: 10.3389/fpsyg.2022.958535.].

A Structural Equation Model of Self-Regulation and Healthy Habits as an Individual Protective Tool in the Context of Epidemics-Evidence From COVID-19.

Objective: The present study aims to explore the mediation role of self-regulation on health-related behaviors adoption or maintenance, mental health, and well-being during the COVID-19 confinement in a sample of adults in Portugal. Design: One-hundred fifty individuals (118 females, 32 males; Mage = 33.57 year; SD = 12.71) filled an online survey to assess self-regulation, healthy behaviors, mental health, and well-being perception, during the early months of the pandemic (June-August, 2020). Main Outcome Measures: Self-regulation capacity, adoption or maintenance of healthy habits, mental health, including stress management, and the perception of one's well-being were evaluated using a structural equation model (SEM). Results: Self-regulation had direct effects on healthy habits and mental health and indirect effects on well-being and mental health mediated by healthy habits. In specific, a positive direct effect on healthy habits (ß = 0.497, p < 0.001) and a negative direct effect on mental health (ß = -0.428, p < 0.001); and a positive indirect effect on well-being perception, mediated by healthy behaviors and mental health (ß = 0.253, p = 0.003), and a negative indirect effect on mental health, mediated by healthy habits (ß = -0.208, p = 0.003). Additionally, healthy habits exerted direct effects on well-being perception and mental health. A positive direct effect on well-being perception (ß = 0.254, p = 0.012), and a negative direct effect on mental health (ß = -0.418, p < 0.001) were further observed. No direct effect of mental health was observed in well-being perception (ß = -0.199, p = 0.068). Finally, a negative correlation was observed between self-regulation and weeks of confinement (r = -0.208, p = 0.021). Conclusion: Self-regulation seems to be a good indicator of adopting a healthy lifestyle and better mental health and well-being in the context of the COVID-19 pandemic. Future preventive actions and interventions to build long-term global preparedness for future health emergencies, such as COVID-19, should explore the importance of self-regulation as an important individual and collective protective factor.

Motor uncoordination and neuropathology in a transgenic mouse model of Machado-Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products.

Machado-Joseph disease (MJD) is a late-onset neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the ataxin-3 protein. We generated two transgenic mouse lineages expressing the expanded human ataxin-3 under the control of the CMV promoter: CMVMJD83 and CMVMJD94, carrying Q83 and Q94 stretches, respectively. Behavioral analysis revealed that the CMVMJD94 transgenic mice developed motor uncoordination, intergenerational instability of the CAG repeat and a tissue-specific increase in the somatic mosaicism of the repeat with aging. Histopathological analysis of MJD mice at early and late stages of the disease revealed neuronal atrophy and astrogliosis in several brain regions; however, we found no signs of microglial activation or neuroinflammatory response prior to the appearance of an overt phenotype. In our model, the appearance of MJD-like symptoms was also not associated with the presence of ataxin-3 cleavage products or intranuclear aggregates. We propose the transgenic CMVMJD94 mice as a useful model to study the early stages in the pathogenesis of MJD and to explore the molecular mechanisms involved in CAG repeat instability.

Mutational analysis of MSX1 and PAX9 genes in Portuguese families with maxillary lateral incisor agenesis.

The observation that certain patterns of tooth agenesis occur more frequently in individuals of the same family may suggest the existence of predisposing genetic factors. The aim of this study was to search for mutations in the PAX9 and MSX1 genes and to investigate their potential association with the maxillary lateral incisor agenesis (MLIA) phenotype in 12 Portuguese families, a total of 52 individuals, 12 probands and 40 relatives (eight of which had MLIA). Twenty-three of the subjects were male and 29 female with an age range of 10-75 years. The control group comprised random DNA samples of 91 Portuguese individuals. Nucleotide alterations were not detected in the coding regions of the MSX1 gene, analysed by single-strand conformation polymorphism and sequencing; in the PAX9 gene, a polymorphism was found that led to transition of G718 to C, implying a change of alanine 240 for proline. However, the differences in the frequencies of the PAX9 gene polymorphism between the probands (67 per cent) and the control population (56 per cent carrying the c allele) were not statistically significant as determined by chi-square test, and the polymorphism did not clearly segregate with the trait in the families. Aggregating the available data, there does not seem to exist a clear association between the alanine 240 for proline variant in the PAX9 gene and the MLIA phenotype. Further studies are required to clarify the basic genetics of MLIA.

Non-pharmacological treatment-related changes of molecular biomarkers in major depressive disorder: A systematic review and meta-analysis

Background: Major depressive disorder (MDD) is a serious mood disorder and leading cause of disability. Despite treatment advances, approximately 30% of individuals with MDD do not achieve adequate clinical response. Better understanding the biological mechanism(s) underlying clinical response to specific psychopharmacological interventions may help fine tune treatments in order to further modulate their underlying mechanisms of action. However, little is known regarding the effect of non-pharmacological treatments (NPTs) on candidate molecular biomarker levels in MDD. This review aims to identify molecular biomarkers that may elucidate NPT response for MDD. Methods: We performed a systematic review and a multilevel linear mixed-effects meta-analyses, and a meta-regression. Searches were performed in PubMed, Scopus, and PsycINFO in October 2020 and July 2021. Results: From 1387 retrieved articles, 17 and six studies were included in the systematic review and meta-analyses, respectively. Although there was little consensus associating molecular biomarker levels with symptomology and/or treatment response, brain metabolites accessed via molecular biomarker-focused neuroimaging techniques may provide promising information on whether an individual with MDD would respond positively to NPTs. Furthermore, non-invasive brain stimulation interventions significantly increased the expression of neurotrophic factors (NTFs) compared to sham/placebo, regardless of add-on pharmacological treatment. Conclusions: NTFs are candidate biomarkers to fine-tune NIBS for MDD treatment. (AU)

Tauroursodeoxycholic Acid Improves Motor Symptoms in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by severe motor symptoms, and currently there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD; however, its effect in PD motor symptoms has never been addressed. In the present work, an extensive behavior analysis was performed to better characterize the MPTP model of PD and to evaluate the effects of TUDCA in the prevention/improvement of mice phenotype. MPTP induced significant alterations in general motor performance paradigms, including increased latency in the motor swimming, adhesive removal and pole tests, as well as altered gait, foot dragging, and tremors. TUDCA administration, either before or after MPTP, significantly reduced the swimming latency, improved gait quality, and decreased foot dragging. Importantly, TUDCA was also effective in the prevention of typical parkinsonian symptoms such as spontaneous activity, ability to initiate movement and tremors. Accordingly, TUDCA prevented MPTP-induced decrease of dopaminergic fibers and ATP levels, mitochondrial dysfunction and neuroinflammation. Overall, MPTP-injected mice presented motor symptoms that are aggravated throughout time, resembling human parkinsonism, whereas PD motor symptoms were absent or mild in TUDCA-treated animals, and no aggravation was observed in any parameter. The thorough demonstration of improvement of PD symptoms together with the demonstration of the pathways triggered by TUDCA supports a subsequent clinical trial in humans and future validation of the application of this bile acid in PD.