Heterozygous loss of Engrailed-1 and α-synucleinopathy (En1/SYN): A dual-hit preclinical mouse model of Parkinson's disease, analyzed with artificial intelligence.

In this study, we develop and validate a new Parkinson's disease (PD) mouse model that can be used to better understand how the disease progresses and to test the effects of new, potentially disease-modifying, PD therapies. Our central hypothesis is that mitochondrial dysfunction intercalates with misfolded α-synuclein (α-syn) accumulation in a vicious cycle, leading to the loss of nigral neurons. Our hypothesis builds on the concept that PD involves multiple molecular insults, including mitochondrial dysfunction and aberrant α-syn handling. We predicted that mitochondrial deficits, due to heterozygous loss of Engrailed-1 (En1+/-), combined with bilateral injections of pathogenic α-syn fibrils (PFFs), will act to generate a highly relevant PD model - the En1/SYN model. Here, En1+/- mice received bilateral intrastriatal stereotaxic injections of either PBS or α-syn fibrils and were analyzed using automated behavioral tests and deep learning-assisted histological analysis at 2, 4, and 6 months post-injection. We observed significant and progressive Lewy body-like inclusion pathology in the amygdala, motor cortex, and cingulate cortex, as well as the loss of tyrosine hydroxylase-positive (TH+) cells in the substantia nigra. The En1/SYN model also exhibited significant motor impairments at 6 months post-injection, which were however not exacerbated as we had expected. Still, this model has a comprehensive number of PD-like phenotypes and is therefore superior when compared to the α-syn PFF or En1+/- models alone.

Entanglement Growth via Splitting of a Few Thermal Quanta.

Quanta splitting is an essential generator of Gaussian entanglement, exemplified by Einstein-Podolsky-Rosen states and apparently the most commonly occurring form of entanglement. In general, it results from the strong pumping of a nonlinear process with a highly coherent and low-noise external drive. In contrast, recent experiments involving efficient trilinear processes in trapped ions and superconducting circuits have opened the complementary possibility to test the splitting of a few thermal quanta. Stimulated by such small thermal energy, a strong degenerate trilinear coupling generates large amounts of nonclassicality, detectable by more than 3 dB of distillable quadrature squeezing. Substantial entanglement can be generated via frequent passive linear coupling to a third mode present in parallel with the trilinear coupling. This new form of entanglement, outside any Gaussian approximation, surprisingly grows with the mean number of split thermal quanta; a quality absent from Gaussian entanglement. Using distillable squeezing we shed light on this new entanglement mechanism for nonlinear bosonic systems.

Formation of templated inclusions in a forebrain α-synuclein mouse model is independent of LRRK2.

Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein share enigmatic roles in the pathobiology of Parkinson's disease (PD). LRRK2 mutations are a common genetic cause of PD which, in addition to neurodegeneration, often present with abnormal deposits of α-synuclein in the form of Lewy-related pathology. As Lewy-related pathology is a prominent neuropathologic finding in sporadic PD, the relationship between LRRK2 and α-synuclein has garnered considerable interest. However, whether and how LRRK2 might influence the accumulation of Lewy-related pathology remains poorly understood. Through stereotactic injection of mouse α-synuclein pre-formed fibrils (PFF), we modeled the spread of Lewy-related pathology within forebrain regions where LRRK2 is most highly expressed. The impact of LRRK2 genotype on the formation of α-synuclein inclusions was evaluated at 1-month post-injection. Neither deletion of LRRK2 nor G2019S LRRK2 knockin appreciably altered the burden of α-synuclein pathology at this early timepoint. These observations fail to provide support for a robust pathophysiologic interaction between LRRK2 and α-synuclein in the forebrain in vivo. There was, however, a modest reduction in microglial activation induced by PFF delivery in the hippocampus of LRRK2 knockout mice, suggesting that LRRK2 may contribute to α-synuclein-induced neuroinflammation. Collectively, our data indicate that the pathological accumulation of α-synuclein in the mouse forebrain is largely independent of LRRK2.

Defining the Riddle in Order to Solve It: There Is More Than One "Parkinson's Disease".

BACKGROUND: More than 200 years after James Parkinsondescribed a clinical syndrome based on his astute observations, Parkinson's disease (PD) has evolved into a complex entity, akin to the heterogeneity of other complex human syndromes of the central nervous system such as dementia, motor neuron disease, multiple sclerosis, and epilepsy. Clinicians, pathologists, and basic science researchers evolved arrange of concepts andcriteria for the clinical, genetic, mechanistic, and neuropathological characterization of what, in their best judgment, constitutes PD. However, these specialists have generated and used criteria that are not necessarily aligned between their different operational definitions, which may hinder progress in solving the riddle of the distinct forms of PD and ultimately how to treat them. OBJECTIVE: This task force has identified current in consistencies between the definitions of PD and its diverse variants in different domains: clinical criteria, neuropathological classification, genetic subtyping, biomarker signatures, and mechanisms of disease. This initial effort for "defining the riddle" will lay the foundation for future attempts to better define the range of PD and its variants, as has been done and implemented for other heterogeneous neurological syndromes, such as stroke and peripheral neuropathy. We strongly advocate for a more systematic and evidence-based integration of our diverse disciplines by looking at well-defined variants of the syndrome of PD. CONCLUSION: Accuracy in defining endophenotypes of "typical PD" across these different but interrelated disciplines will enable better definition of variants and their stratification in therapeutic trials, a prerequisite for breakthroughs in the era of precision medicine. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dopaminergic neurodegeneration induced by Parkinson's disease-linked G2019S LRRK2 is dependent on kinase and GTPase activity.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of late-onset, autosomal-dominant familial Parkinson's disease (PD). LRRK2 functions as both a kinase and GTPase, and PD-linked mutations are known to influence both enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage in culture models, the mechanisms underlying these pathogenic effects remain uncertain. Rodent models containing familial LRRK2 mutations often lack robust PD-like neurodegenerative phenotypes. Here, we develop a robust preclinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of human LRRK2 harboring the most common G2019S mutation. In this model, G2019S LRRK2 induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or administration of the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the robust destabilization of human LRRK2 protein in the brain relative to endogenous LRRK2. Our study further demonstrates that G2019S LRRK2-induced dopaminergic neurodegeneration critically requires normal GTPase activity, as hypothesis-testing mutations that increase GTP hydrolysis or impair GTP-binding activity provide neuroprotection although via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent preclinical model of LRRK2-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets.

Understanding the contributions of VPS35 and the retromer in neurodegenerative disease.

Perturbations of the endolysosomal pathway have been suggested to play an important role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD). Specifically, VPS35 and the retromer complex play an important role in the endolysosomal system and are implicated in the pathophysiology of these diseases. A single missense mutation in VPS35, Asp620Asn (D620N), is known to cause late-onset, autosomal dominant familial PD. In this review, we focus on the emerging role of the PD-linked D620N mutation in causing retromer dysfunction and dissect its implications in neurodegeneration. Additionally, we will discuss how VPS35 and the retromer are linked to AD, amyotrophic lateral sclerosis, and primary tauopathies. Interestingly, reduced levels of VPS35 and other retromer components have been observed in post-mortem brain tissue, suggesting a role for the retromer in the pathophysiology of these diseases. This review will provide a comprehensive dive into the mechanisms of VPS35 dysfunction in neurodegenerative diseases. Furthermore, we will highlight outstanding questions in the field and the retromer as a therapeutic target for neurodegenerative disease at large.

Thermally induced entanglement of atomic oscillators.

Laser cooled ions trapped in a linear Paul trap are long-standing ideal candidates for realizing quantum simulation, especially of many-body systems. The properties that contribute to this also provide the opportunity to demonstrate unexpected quantum phenomena in few-body systems. A pair of ions interacting in such traps exchange vibrational quanta through the Coulomb interaction. This linear interaction can be anharmonically modulated by an elementary coupling to the internal two-level structure of one of the ions. Driven by thermal energy in the passively coupled oscillators, which are themselves coupled to the internal ground states of the ions, the nonlinear interaction autonomously and unconditionally generates entanglement between the mechanical modes of the ions. We examine this counter-intuitive thermally induced entanglement for several experimentally feasible model systems and propose parameter regimes where state-of-the-art trapped ion systems can produce such phenomena. In addition, we demonstrate a multiqubit enhancement of such thermally induced entanglements.

New horizons for caring for people with dementia in hospital: the DEMENTIA CARE pointers for service change.

Approximately two-thirds of hospital admissions are older adults and almost half of these are likely to have some form of dementia. People with dementia are not only at an increased risk of adverse outcomes once admitted, but the unfamiliar environment and routinised practices of the wards and acute care can be particularly challenging for them, heightening their confusion, agitation and distress further impacting the ability to optimise their care. It is well established that a person-centred care approach helps alleviate some of the unfamiliar stress but how to embed this in the acute-care setting remains a challenge. In this article, we highlight the challenges that have been recognised in this area and put forward a set of evidence-based 'pointers for service change' to help organisations in the delivery of person-centred care. The DEMENTIA CARE pointers cover areas of: dementia awareness and understanding, education and training, modelling of person-centred care by clinical leaders, adapting the environment, teamwork (not being alone), taking the time to 'get to know', information sharing, access to necessary resources, communication, involving family (ask family), raising the profile of dementia care, and engaging volunteers. The pointers extend previous guidance, by recognising the importance of ward cultures that prioritise dementia care and institutional support that actively seeks to raise the profile of dementia care. The pointers provide a range of simple to more complex actions or areas for hospitals to help implement person-centred care approaches; however, embedding them within the organisational cultures of hospitals is the next challenge.

Parkinson's disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration.

Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene represent a cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, D620N, is considered pathogenic based upon its segregation with disease in multiple families with PD. At present, the mechanism(s) by which familial VPS35 mutations precipitate neurodegeneration in PD are poorly understood. Here, we employ a germline D620N VPS35 knockin (KI) mouse model of PD to formally establish the age-related pathogenic effects of the D620N mutation at physiological expression levels. Our data demonstrate that a heterozygous or homozygous D620N mutation is sufficient to reproduce key neuropathological hallmarks of PD as indicated by the progressive degeneration of nigrostriatal pathway dopaminergic neurons and widespread axonal pathology. Unexpectedly, endogenous D620N VPS35 expression induces robust tau-positive somatodendritic pathology throughout the brain as indicated by abnormal hyperphosphorylated and conformation-specific tau, which may represent an important and early feature of mutant VPS35-induced neurodegeneration in PD. In contrast, we find no evidence for α-synuclein-positive neuropathology in aged VPS35 KI mice, a hallmark of Lewy body pathology in PD. D620N VPS35 expression also fails to modify the lethal neurodegenerative phenotype of human A53T-α-synuclein transgenic mice. Finally, by crossing VPS35 KI and null mice, our data demonstrate that a single D620N VPS35 allele is sufficient for survival and early maintenance of dopaminergic neurons, indicating that the D620N VPS35 protein is fully functional. Our data raise the tantalizing possibility of a pathogenic interplay between mutant VPS35 and tau for inducing neurodegeneration in PD.

Multiple genetic pathways regulating lifespan extension are neuroprotective in a G2019S LRRK2 nematode model of Parkinson's disease.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of late-onset, familial Parkinson's disease (PD), and LRRK2 variants are associated with increased risk for sporadic PD. While advanced age represents the strongest risk factor for disease development, it remains unclear how different age-related pathways interact to regulate LRRK2-driven late-onset PD. In this study, we employ a C. elegans model expressing PD-linked G2019S LRRK2 to examine the interplay between age-related pathways and LRRK2-induced dopaminergic neurodegeneration. We find that multiple genetic pathways that regulate lifespan extension can provide robust neuroprotection against mutant LRRK2. However, the level of neuroprotection does not strictly correlate with the magnitude of lifespan extension, suggesting that lifespan can be experimentally dissociated from neuroprotection. Using tissue-specific RNAi, we demonstrate that lifespan-regulating pathways, including insulin/insulin-like growth factor-1 (IGF-1) signaling, target of rapamycin (TOR), and mitochondrial respiration, can be directly manipulated in neurons to mediate neuroprotection. We extend this finding for AGE-1/PI3K, where pan-neuronal versus dopaminergic neuronal restoration of AGE-1 reveals both cell-autonomous and non-cell-autonomous neuroprotective mechanisms downstream of insulin signaling. Our data demonstrate the importance of distinct lifespan-regulating pathways in the pathogenesis of LRRK2-linked PD, and suggest that extended longevity is broadly neuroprotective via the actions of these pathways at least in part within neurons. This study further highlights the complex interplay that occurs between cells and tissues during organismal aging and disease manifestation.

No evidence synthesis about me without me: Involving young people in the conduct and dissemination of a complex evidence synthesis.

OBJECTIVES: To describe and reflect on the methods and influence of involvement of young people with lived experience within a complex evidence synthesis. STUDY DESIGN AND SETTING: Linked syntheses of quantitative and qualitative systematic reviews of evidence about interventions to improve the mental health of children and young people (CYP) with long-term physical conditions (LTCs). METHODS: Involvement was led by an experienced patient and public involvement in research lead. Young people with long-term physical conditions and mental health issues were invited to join a study-specific Children and Young People's Advisory Group (CYPAG). The CYPAG met face to face on four occasions during the project with individuals continuing to contribute to dissemination following report submission. RESULTS: Eight young people joined the CYPAG. Their views and experiences informed (a) a systematic review evaluating the effectiveness of interventions intended to improve the mental health of CYP with LTCs, (b) a systematic review exploring the experiences of interventions intended to improve the mental well-being of CYP with LTCs and (c) an overarching synthesis. The CYPAG greatly contributed to the team's understanding and appreciation of the wider context of the research. The young people found the experience of involvement empowering and felt they would use the knowledge they had gained about the research process in the future. CONCLUSION: Creating an environment that enabled meaningful engagement between the research team and the CYPAG had a beneficial influence on the young people themselves, as well as on the review process and the interpretation, presentation and dissemination of findings.

Bariatric Surgical Alterations in Tolerability, Enjoyment and Cravings in the Diet (BSATED) instrument: A new scale to measure food preferences following bariatric surgery.

Bariatric surgery is associated with changing food preferences, but it is not known whether these changes differ by type of operation or are associated with weight loss. The current study presents validation results for a new 27-item scale, Bariatric Surgical Alterations in Tolerability, Enjoyment and Cravings in the Diet (BSATED). This scale measured enjoyment, craving, and intolerance changes for nine food and beverage categories common to dietary habits in the Southern California region of the U.S. one year following bariatric surgery in the Bariatric Experience Long Term (BELONG) study. Validation of BSATED was done using exploratory factor analyses, construct validity with other conceptually related survey instruments, and criterion validity using hypothesized differences for operation type and percent total weight loss (%TWL) at 12-18 months after surgery. Participants (n = 999) were 86% female, 41% non-Hispanic White, with a mean age of 43.1 ± 11.3 years and a body mass index (BMI) of 43.4 ± 6.8 kg/m2 at the time of surgery. Participants reported less enjoyment and craving for high-fat meats (62%), grains (54%), candy and other desserts (e.g. candy bars, chocolate, ice cream) (52%), and sweet baked goods (48%) 12 months after surgery. These changes were more common among participants undergoing Roux-en-Y gastric bypass (RYGB) compared to those receiving sleeve gastrectomy (SG). Participants who reported decreased enjoyment and craving for foods and beverages that post-bariatric patients are counseled to reduce or avoid had greater %TWL at 12-18 months following surgery (p < .001 and p = .003 respectively). The foods and beverages in BSATED that post-bariatric patients are counseled to reduce or avoid could be used to understand how changes in enjoyment, craving and tolerability of these foods/beverages contribute to weight loss following surgery.

Parkin mediates the ubiquitination of VPS35 and modulates retromer-dependent endosomal sorting.

Mutations in a number of genes cause familial forms of Parkinson's disease (PD), including mutations in the vacuolar protein sorting 35 ortholog (VPS35) and parkin genes. In this study, we identify a novel functional interaction between parkin and VPS35. We demonstrate that parkin interacts with and robustly ubiquitinates VPS35 in human neural cells. Familial parkin mutations are impaired in their ability to ubiquitinate VPS35. Parkin mediates the attachment of an atypical poly-ubiquitin chain to VPS35 with three lysine residues identified within the C-terminal region of VPS35 that are covalently modified by ubiquitin. Notably, parkin-mediated VPS35 ubiquitination does not promote the proteasomal degradation of VPS35. Furthermore, parkin does not influence the steady-state levels or turnover of VPS35 in neural cells and VPS35 levels are normal in the brains of parkin knockout mice. These data suggest that ubiquitination of VPS35 by parkin may instead serve a non-degradative cellular function potentially by regulating retromer-dependent sorting. Accordingly, we find that components of the retromer-associated WASH complex are markedly decreased in the brain of parkin knockout mice, suggesting that parkin may modulate WASH complex-dependent retromer sorting. Parkin gene silencing in primary cortical neurons selectively disrupts the vesicular sorting of the autophagy receptor ATG9A, a WASH-dependent retromer cargo. Parkin is not required for dopaminergic neurodegeneration induced by the expression of PD-linked D620N VPS35 in mice, consistent with VPS35 being located downstream of parkin function. Our data reveal a novel functional interaction of parkin with VPS35 that may be important for retromer-mediated endosomal sorting and PD.

G2019S LRRK2 enhances the neuronal transmission of tau in the mouse brain.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). LRRK2 mutations typically give rise to Lewy pathology in the brains of PD subjects yet can induce tau-positive neuropathology in some cases. The pathological interaction between LRRK2 and tau remains poorly defined. To explore this interaction in vivo, we crossed a well-characterized human P301S-tau transgenic mouse model of tauopathy with human G2019S-LRRK2 transgenic mice or LRRK2 knockout (KO) mice. We find that endogenous or pathogenic LRRK2 expression has minimal effects on the steady-state levels, solubility and abnormal phosphorylation of human P301S-tau throughout the mouse brain. We next developed a new model of tauopathy by delivering AAV2/6 vectors expressing human P301S-tau to the hippocampal CA1 region of G2019S-LRRK2 transgenic or LRRK2 KO mice. P301S-tau expression induces hippocampal tau pathology and marked degeneration of CA1 pyramidal neurons in mice, however, this occurs independently of endogenous or pathogenic LRRK2 expression. We further developed new AAV2/6 vectors co-expressing human WT-tau and GFP to monitor the neuron-to-neuron transmission of tau within defined hippocampal neuronal circuits. While endogenous LRRK2 is not required for tau transmission, we find that G2019S-LRRK2 markedly enhances the neuron-to-neuron transmission of tau in mice. Our data suggest that mutant tau-induced neuropathology occurs independently of LRRK2 expression in two mouse models of tauopathy but identifies a novel pathogenic role for G2019S-LRRK2 in promoting the neuronal transmission of WT-tau protein. These findings may have important implications for understanding the development of tau neuropathology in LRRK2-linked PD brains.

Activity interventions to improve the experience of care in hospital for people living with dementia: a systematic review.

BACKGROUND: An increasingly high number of patients admitted to hospital have dementia. Hospital environments can be particularly confusing and challenging for people living with dementia (Plwd) impacting their wellbeing and the ability to optimize their care. Improving the experience of care in hospital has been recognized as a priority, and non-pharmacological interventions including activity interventions have been associated with improved wellbeing and behavioral outcomes for Plwd in other settings. This systematic review aimed at evaluating the effectiveness of activity interventions to improve experience of care for Plwd in hospital. METHODS: Systematic searches were conducted in 16 electronic databases up to October 2019. Reference lists of included studies and forward citation searching were also conducted. Quantitative studies reporting comparative data for activity interventions delivered to Plwd aiming to improve their experience of care in hospital were included. Screening for inclusion, data extraction and quality appraisal were performed independently by two reviewers with discrepancies resolved by discussion with a third where necessary. Standardized mean differences (SMDs) were calculated where possible to support narrative statements and aid interpretation. RESULTS: Six studies met the inclusion criteria (one randomized and five non-randomized uncontrolled studies) including 216 Plwd. Activity interventions evaluated music, art, social, psychotherapeutic, and combinations of tailored activities in relation to wellbeing outcomes. Although studies were generally underpowered, findings indicated beneficial effects of activity interventions with improved mood and engagement of Plwd while in hospital, and reduced levels of responsive behaviors. Calculated SMDs ranged from very small to large but were mostly statistically non-significant. CONCLUSIONS: The small number of identified studies indicate that activity-based interventions implemented in hospitals may be effective in improving aspects of the care experience for Plwd. Larger well-conducted studies are needed to fully evaluate the potential of this type of non-pharmacological intervention to improve experience of care in hospital settings, and whether any benefits extend to staff wellbeing and the wider ward environment.

Effectiveness of pharmacist home visits for individuals at risk of medication-related problems: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Medication mismanagement is a major cause of both hospital admission and nursing home placement of frail older adults. Medication reviews by community pharmacists aim to maximise therapeutic benefit but also minimise harm. Pharmacist-led medication reviews have been the focus of several systematic reviews, but none have focussed on the home setting. REVIEW METHODS: To determine the effectiveness of pharmacist home visits for individuals at risk of medication-related problems we undertook a systematic review and meta-analysis of randomised controlled trials (RCTs). Thirteen databases were searched from inception to December 2018. Forward and backward citation of included studies was also performed. Articles were screened for inclusion independently by two reviewers. Randomised controlled studies of home visits by pharmacists for individuals at risk of medication-related problems were eligible for inclusion. Data extraction and quality appraisal were performed by one reviewer and checked by a second. Random-effects meta-analyses were performed where sufficient data allowed and narrative synthesis summarised all remaining data. RESULTS: Twelve RCTs (reported in 15 articles), involving 3410 participants, were included in the review. The frequency, content and purpose of the home visit varied considerably. The data from eight trials were suitable for meta-analysis of the effects on hospital admissions and mortality, and from three trials for the effects on quality of life. Overall there was no evidence of reduction in hospital admissions (risk ratio (RR) of 1.01 (95%CI 0.86 to 1.20, I2 = 69.0%, p = 0.89; 8 studies, 2314 participants)), or mortality (RR of 1.01 (95%CI 0.81 to 1.26, I2 = 0%, p = 0.94; 8 studies, 2314 participants)). There was no consistent evidence of an effect on quality of life, medication adherence or knowledge. CONCLUSION: A systematic review of twelve RCTs assessing the impact of pharmacist home visits for individuals at risk of medication related problems found no evidence of effect on hospital admission or mortality rates, and limited evidence of effect on quality of life. Future studies should focus on using more robust methods to assess relevant outcomes.

Emotional disorder and absence from school: findings from the 2004 British Child and Adolescent Mental Health Survey.

Emotional disorder may be associated with absence from school, but the existing evidence is methodologically weak. We studied the relationships between anxiety, depression and emotional difficulties, and school absence (total, authorised and unauthorised) using data from the 2004 British Child and Adolescent Mental Health Survey (BCAMHS). The BCAMHS was a cross-sectional, community survey of 7977 5- to 16-year-olds. Emotional disorder was assessed using the Development and Wellbeing Assessment (DAWBA), and emotional difficulties using the Strengths and Difficulties Questionnaire (SDQ) completed by teachers and parents. Teachers reported days absent in the previous school term. Multivariable negative binomial regression was used to examine the impact of emotional disorder and difficulties on absence. Age, gender and general health were explored as moderators. Anxiety, depression and emotional difficulties were associated with higher rates of all types of absence [rate ratios for total absence: anxiety 1.69 (1.39-2.06) p < 0.001; depression 3.40 (2.46-4.69) p < 0.001; parent-reported emotional difficulties 1.07 (1.05-1.10) p < 0.001; teacher-reported emotional difficulties 1.10 (1.08-1.13) p < 0.001]. The strongest association was observed for depression and unauthorised absence. Relationships were stronger for secondary compared to primary school children. Health and educational professionals should be aware that children with poor attendance may be experiencing emotional ill health, regardless of absence type. The absence may provide a useful tool to identify those who require additional mental health support. Findings highlight the widespread burden of emotional disorder and the need to support those with emotional ill health in continuing to access education.

Secondary school practitioners' beliefs about risk factors for school attendance problems: a qualitative study.

School staff have an important role to play in identifying and assisting pupils who require additional support to regularly attend school, but their beliefs about risk factors might influence their decisions regarding intervention. This qualitative study investigated educational practitioners' beliefs about risk factors for attendance problems. Sixteen practitioners from three secondary schools were interviewed via focus groups. Data were analysed using thematic analysis. Practitioners identified risk factors related to the individual, their family, peers and school. Poor mental health was identified as a risk factor, but practitioners primarily focused on anxiety rather than other mental health problems like depression or behavioural disorders. The overall perception was that school factors were less important than individual, family and peer factors. Implications include a need for increased awareness of the role of school factors in attendance problems, focus on promoting positive peer and pupil-teacher relationships, and collaborative working between young people, families and schools.

Time course and magnitude of alpha-synuclein inclusion formation and nigrostriatal degeneration in the rat model of synucleinopathy triggered by intrastriatal α-synuclein preformed fibrils.

Animal models that accurately recapitulate the accumulation of alpha-synuclein (α-syn) inclusions, progressive neurodegeneration of the nigrostriatal system and motor deficits can be useful tools for Parkinson's disease (PD) research. The preformed fibril (PFF) synucleinopathy model in rodents generally displays these PD-relevant features, however, the magnitude and predictability of these events is far from established. We therefore sought to optimize the magnitude of α-syn accumulation and nigrostriatal degeneration, and to understand the time course of both. Rats were injected unilaterally with different quantities of α-syn PFFs (8 or 16 µg of total protein) into striatal sites selected to concentrate α-syn inclusion formation in the substantia nigra pars compacta (SNpc). Rats displayed an α-syn PFF quantity-dependent increase in the magnitude of ipsilateral SNpc inclusion formation at 2 months and bilateral loss of nigral dopamine neurons at 6 months. Unilateral 16 µg PFF injection also resulted in modest sensorimotor deficits in forelimb adjusting steps associated with degeneration at 6 months. Bilateral injection of 16 µg α-syn PFFs resulted in symmetric bilateral degeneration equivalent to the ipsilateral nigral degeneration observed following unilateral 16 µg PFF injection (~50% loss). Bilateral PFF injections additionally resulted in alterations in several gait analysis parameters. These α-syn PFF parameters can be applied to generate a reproducible synucleinopathy model in rats with which to study pathogenic mechanisms and vet potential disease-modifying therapies.

Parkin functionally interacts with PGC-1α to preserve mitochondria and protect dopaminergic neurons.

To understand the cause of Parkinson's disease (PD), it is important to determine the functional interactions between factors linked to the disease. Parkin is associated with autosomal recessive early-onset PD, and controls the transcription of PGC-1α, a master regulator of mitochondrial biogenesis. These two factors functionally interact to regulate the turnover and quality of mitochondria, by increasing both mitophagic activity and mitochondria biogenesis. In cortical neurons, co-expressing PGC-1α and Parkin increases the number of mitochondria, enhances maximal respiration, and accelerates the recovery of the mitochondrial membrane potential following mitochondrial uncoupling. PGC-1α enhances Mfn2 transcription, but also leads to increased degradation of the Mfn2 protein, a key ubiquitylation target of Parkin on mitochondria. In vivo, Parkin has significant protective effects on the survival and function of nigral dopaminergic neurons in which the chronic expression of PGC-1α is induced. Ultrastructural analysis shows that these two factors together control the density of mitochondria and their interaction with the endoplasmic reticulum. These results highlight the combined effects of Parkin and PGC-1α in the maintenance of mitochondrial homeostasis in dopaminergic neurons. These two factors synergistically control the quality and function of mitochondria, which is important for the survival of neurons in Parkinson's disease.