More than a number: Incorporating the aged phenotype to improve in vitro and in vivo modeling of neurodegenerative disease.

Age is the number one risk factor for developing a neurodegenerative disease (ND), such as Alzheimer's disease (AD) or Parkinson's disease (PD). With our rapidly ageing world population, there will be an increased burden of ND and need for disease-modifying treatments. Currently, however, translation of research from bench to bedside in NDs is poor. This may be due, at least in part, to the failure to account for the potential effect of ageing in preclinical modelling of NDs. While ageing can impact upon physiological response in multiple ways, only a limited number of preclinical studies of ND have incorporated ageing as a factor of interest. Here, we evaluate the aged phenotype and highlight the critical, but unmet, need to incorporate aspects of this phenotype into both the in vitro and in vivo models used in ND research. Given technological advances in the field over the past several years, we discuss how these could be harnessed to create novel models of ND that more readily incorporate aspects of the aged phenotype. This includes a recently described in vitro panel of ageing markers, which could help lead to more standardised models and improve reproducibility across studies. Importantly, we cannot assume that young cells or animals yield the same responses as seen in the context of ageing; thus, an improved understanding of the biology of ageing, and how to appropriately incorporate this into the modelling of ND, will ensure the best chance for successful translation of new therapies to the aged patient.

Protective roles of peroxiporins AQP0 and AQP11 in human astrocyte and neuronal cell lines in response to oxidative and inflammatory stressors.

In addition to aquaporin (AQP) classes AQP1, AQP4 and AQP9 known to be expressed in mammalian brain, our recent transcriptomic analyses identified AQP0 and AQP11 in human cortex and hippocampus at levels correlated with age and Alzheimer's disease (AD) status; however, protein localization remained unknown. Roles of AQP0 and AQP11 in transporting hydrogen peroxide (H2O2) in lens and kidney prompted our hypothesis that up-regulation in brain might similarly be protective. Established cell lines for astroglia (1321N1) and neurons (SHSY5Y, differentiated with retinoic acid) were used to monitor changes in transcript levels for human AQPs (AQP0 to AQP12) in response to inflammation (simulated with 10-100 ng/ml lipopolysaccharide [LPS], 24 h), and hypoxia (5 min N2, followed by 0 to 24 h normoxia). AQP transcripts up-regulated in both 1321N1 and SHSY5Y included AQP0, AQP1 and AQP11. Immunocytochemistry in 1321N1 cells confirmed protein expression for AQP0 and AQP11 in plasma membrane and endoplasmic reticulum; AQP11 increased 10-fold after LPS and AQP0 increased 0.3-fold. In SHSY5Y cells, AQP0 expression increased 0.2-fold after 24 h LPS; AQP11 showed no appreciable change. Proposed peroxiporin roles were tested using melondialdehyde (MDA) assays to quantify lipid peroxidation levels after brief H2O2. Boosting peroxiporin expression by LPS pretreatment lowered subsequent H2O2-induced MDA responses (∼50%) compared with controls; conversely small interfering RNA knockdown of AQP0 in 1321N1 increased lipid peroxidation (∼17%) after H2O2, with a similar trend for AQP11 siRNA. Interventions that increase native brain peroxiporin activity are promising as new approaches to mitigate damage caused by aging and neurodegeneration.

Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment.

We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37-38 deletion male (Thoc2Δ/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2Δ/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.

Anatomical distribution of Fyn kinase in the human brain in Parkinson's disease.

INTRODUCTION: Fyn kinase is an Src family kinase (SFK) widely expressed in many tissues, including the CNS. Recently, Fyn kinase activation has been associated with pathological mechanisms underlying neurodegenerative diseases and, as such, the role of Fyn dysfunction is under investigation. In particular, Fyn is implicated as a major upstream regulator of neuroinflammation in Parkinson's Disease (PD). Chronic neuroinflammation has been observed not just in the substantia nigra (SN), but also in several key regions of the brain, with disruption associated with symptoms presentation in PD. This study aimed to characterise the anatomical distribution of Fyn in key brain regions affected in PD, namely the prefrontal cortex, hippocampus, striatum and SN. METHODS: Fresh and fixed post-mortem PD brain samples (n = 10) were collected and compared with neurologically healthy age-matched controls (n = 7) to assess markers of Fyn activity and neuroinflammation. RESULTS: Increased Fyn phosphorylation was observed in SN and striatum of post-mortem samples from PD patients compared with controls. No such increase was observed in the prefrontal cortex or hippocampus. In contrast with previous findings, no increase in microglial activation or astrocyte reactivity was observed in PD brains across regions. CONCLUSION: Taken together, these results indicate that Fyn dysfunction may be involved in the pathological processes observed in PD; however, this appears to be independent of inflammatory mechanisms. Further investigations are required to elucidate if increased Fyn activity is a potential cause or consequence of pathological processing in PD.

Neuronanomedicine for Alzheimer's and Parkinson's disease: Current progress and a guide to improve clinical translation.

Neuronanomedicine is an emerging multidisciplinary field that aims to create innovative nanotechnologies to treat major neurodegenerative disorders, such as Alzheimer's (AD) and Parkinson's disease (PD). A key component of neuronanomedicine are nanoparticles, which can improve drug properties and demonstrate enhanced safety and delivery across the blood-brain barrier, a major improvement on existing therapeutic approaches. In this review, we critically analyze the latest nanoparticle-based strategies to modify underlying disease pathology to slow or halt AD/PD progression. We find that a major roadblock for neuronanomedicine translation to date is a poor understanding of how nanoparticles interact with biological systems (i.e., bio-nano interactions), which is partly due to inconsistent reporting in published works. Accordingly, this review makes a set of specific recommendations to help guide researchers to harness the unique properties of nanoparticles and thus realise breakthrough treatments for AD/PD.

Leakage beyond the primary lesion: A temporal analysis of cerebrovascular dysregulation at sites of hippocampal secondary neurodegeneration following cortical photothrombotic stroke.

We have previously demonstrated that a cortical stroke causes persistent impairment of hippocampal-dependent cognitive tasks concomitant with secondary neurodegenerative processes such as amyloid-ß accumulation in the hippocampus, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid-ß around cerebral vessels may lead to cerebrovascular structural changes, neurovascular dysfunction, and disruption of blood-brain barrier integrity. However, there is limited knowledge about the temporal changes of hippocampal cerebrovasculature after cortical stroke. In the current study, we aimed to characterise the spatiotemporal cerebrovascular changes after cortical stroke. This was done using the photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Cerebrovascular morphology as well as the co-localisation of amyloid-ß with vasculature and blood-brain barrier integrity were assessed in the cortex and hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed transient cerebrovascular remodelling in the peri-infarct area up to 28 days post-stroke. Importantly, the cerebrovascular changes were extended beyond the peri-infarct region to the ipsilateral hippocampus and were sustained out to 84 days post-stroke. When investigating vessel diameter, we showed a decrease at 84 days in the peri-infarct and CA1 regions that were exacerbated in vessels with amyloid-ß deposition. Lastly, we showed sustained vascular leakage in the peri-infarct and ipsilateral hippocampus, indicative of a compromised blood-brain-barrier. Our findings indicate that hippocampal vasculature may represent an important therapeutic target to mitigate the progression of post-stroke cognitive impairment.

"Chemobrain" in childhood cancer survivors-the impact on social, academic, and daily living skills: a qualitative systematic review.

PURPOSE: To examine children's experiences of chemotherapy-induced cognitive impairment--colloquially "chemobrain"--and the impact on children's social, academic, and daily living skills via a qualitative systematic review. Experiencing chemotherapy as a child, when the brain is still developing, may cause lifelong detriment to survivors' lives. There is a significant gap in understanding their lived experience, including the self-identified barriers that children face following treatment. Such a gap can only be fully bridged by listening to the child's own voice and/or parent proxy report through an exploration of the qualitative research literature. METHODS: A search of MEDLINE, Embase, PsycINFO, and CINAHL databases was conducted. Inclusion criteria were qualitative studies with a focus on children (0-18 years) during and/or following chemotherapy treatment and explored children's experiences of chemobrain. RESULTS: Two synthesized findings were identified from six studies. (1) Chemobrain has an academic and psychosocial impact, which may not be understood by education providers. (2) Children and their parents have concerns about their reintegration and adaptation to school, social lives, and their future selves as independent members of society. Children's experiences primarily related to changes in their academic and social functioning. CONCLUSION: This review highlights two important considerations: (1) the lived experiences of pediatric childhood cancer survivors guiding where future interventions should be targeted, and (2) a need to perform more qualitative research studies in this area, as well as to improve the quality of reporting among the existing literature, given that this is a current gap in the field.

Chronic motor performance following different traumatic brain injury severity-A systematic review.

Introduction: Traumatic brain injury (TBI) is now known to be a chronic disease, causing ongoing neurodegeneration and linked to increased risk of neurodegenerative motor diseases, such as Parkinson's disease and amyotrophic lateral sclerosis. While the presentation of motor deficits acutely following traumatic brain injury is well-documented, however, less is known about how these evolve in the long-term post-injury, or how the initial severity of injury affects these outcomes. The purpose of this review, therefore, was to examine objective assessment of chronic motor impairment across the spectrum of TBI in both preclinical and clinical models. Methods: PubMed, Embase, Scopus, and PsycINFO databases were searched with a search strategy containing key search terms for TBI and motor function. Original research articles reporting chronic motor outcomes with a clearly defined TBI severity (mild, repeated mild, moderate, moderate-severe, and severe) in an adult population were included. Results: A total of 97 studies met the inclusion criteria, incorporating 62 preclinical and 35 clinical studies. Motor domains examined included neuroscore, gait, fine-motor, balance, and locomotion for preclinical studies and neuroscore, fine-motor, posture, and gait for clinical studies. There was little consensus among the articles presented, with extensive differences both in assessment methodology of the tests and parameters reported. In general, an effect of severity was seen, with more severe injury leading to persistent motor deficits, although subtle fine motor deficits were also seen clinically following repeated injury. Only six clinical studies investigated motor outcomes beyond 10 years post-injury and two preclinical studies to 18-24 months post-injury, and, as such, the interaction between a previous TBI and aging on motor performance is yet to be comprehensively examined. Conclusion: Further research is required to establish standardized motor assessment procedures to fully characterize chronic motor impairment across the spectrum of TBI with comprehensive outcomes and consistent protocols. Longitudinal studies investigating the same cohort over time are also a key for understanding the interaction between TBI and aging. This is particularly critical, given the risk of neurodegenerative motor disease development following TBI.

Unexpected Classes of Aquaporin Channels Detected by Transcriptomic Analysis in Human Brain Are Associated with Both Patient Age and Alzheimer's Disease Status.

The altered expression of known brain Aquaporin (AQP) channels 1, 4 and 9 has been correlated with neuropathological AD progression, but possible roles of other AQP classes in neurological disease remain understudied. The levels of transcripts of all thirteen human AQP subtypes were compared in healthy and Alzheimer's disease (AD) brains by statistical analyses of microarray RNAseq expression data from the Allen Brain Atlas database. Previously unreported, AQPs 0, 6 and 10, are present in human brains at the transcript level. Three AD-affected brain regions, hippocampus (HIP), parietal cortex (PCx) and temporal cortex (TCx), were assessed in three subgroups: young controls (n = 6, aged 24-57); aged controls (n = 26, aged 78-99); and an AD cohort (n = 12, aged 79-99). A significant positive correlation (p < 10-10) was seen for AQP transcript levels as a function of the subject's age in years. Differential expressions correlated with brain region, age, and AD diagnosis, particularly between the HIP and cortical regions. Interestingly, three classes of AQPs (0, 6 and 8) upregulated in AD compared to young controls are permeable to H2O2. Of these, AQPs 0 and 8 were increased in TCx and AQP6 in HIP, suggesting a role of AQPs in AD-related oxidative stress. The outcomes here are the first to demonstrate that the expression profile of AQP channels in the human brain is more diverse than previously thought, and transcript levels are influenced by both age and AD status. Associations between reactive oxygen stress and neurodegenerative disease risk highlight AQPs 0, 6, 8 and 10 as potential therapeutic targets.

The effectiveness of anti-inflammatory agents in reducing chemotherapy-induced cognitive impairment in preclinical models - A systematic review.

Chemotherapy-induced cognitive impairment (CICI) is a debilitating condition resulting from chemotherapy administration for cancer treatment. CICI is characterised by various cognitive impairments, including issues with learning, memory, and concentration, impacting quality of life. Several neural mechanisms are proposed to drive CICI, including inflammation, therefore, anti-inflammatory agents could ameliorate such impairments. Research is still in the preclinical stage; however, the efficacy of anti-inflammatories to reduce CICI in animal models is unknown. Therefore, a systematic review was conducted, with searches performed in PubMed, Scopus, Embase, PsycInfo and Cochrane Library. A total of 64 studies were included, and of the 50 agents identified, 41 (82%) reduced CICI. Interestingly, while non-traditional anti-inflammatory agents and natural compounds reduced impairment, the traditional agents were unsuccessful. Such results must be taken with caution due to the heterogeneity observed in terms of methods employed. Nevertheless, preliminary evidence suggests anti-inflammatory agents could be beneficial for treating CICI, although it may be critical to think beyond the use of traditional anti-inflammatories when considering which specific compounds to prioritise in development.

Initial Severity of Injury Has Little Effect on the Temporal Profile of Long-Term Deficits in Locomotion, Anxiety, and Cognitive Function After Diffuse Traumatic Brain Injury.

Traumatic brain injury (TBI) is associated with persistent impairments in multiple domains, including cognitive and neuropsychiatric function. Previous literature has suggested that the risk of such impairments may differ as a function of the initial severity of injury, with moderate-severe TBI (msTBI) associated with more severe cognitive dysfunction and mild TBI (mTBI) associated with a higher risk of developing an anxiety disorder. Despite this, relatively few pre-clinical studies have investigated the time course of behavioral change after different severities of injury. The current study compared the temporal profile of functional deficits incorporating locomotion, cognition, and anxiety up to 12 months post-injury after an mTBI, repeated mild TBI (rmTBI), and single msTBI in an experimental model of diffuse TBI. Injury appeared to alter the effect of aging on locomotor activity, with both msTBI and rmTBI rats showing a decrease in locomotion at 12 months relative to their earlier performance on the task, an effect not observed in shams or after a single mTBI. Further, mTBI seemed to be associated with decreased anxiety over time, as measured by increased time spent in the open arm of the elevated plus maze from 3 to 12 months post-injury. No significant findings were observed on spatial memory or volumetric magnetic resonance imaging. Future studies will need to use a more comprehensive behavioral battery, capable of capturing subtle alterations in function, and longer time points, following rats into old age, in order to more fully assess the evolution of persistent behavioral deficits in key domains after different severities of TBI, as well as their accompanying neuroimaging changes. Given the prevalence and significance of such deficits post-TBI for a person's quality of life, as well as the elevated risk of neurodegenerative disease post-injury, such investigations may play a critical role in identifying optimal windows of therapeutic intervention post-injury.

Development and Co-design of NeuroOrb: A Novel "Serious Gaming" System Targeting Cognitive Impairment in Parkinson's Disease.

Whilst Parkinson's disease (PD) is typically thought of as a motor disease, a significant number of individuals also experience cognitive impairment (CI), ranging from mild-CI to dementia. One technique that may prove effective in delaying the onset of CI in PD is cognitive training (CT); however, evidence to date is variable. This may be due to the implementation of CT in this population, with the motor impairments of PD potentially hampering the ability to use standard equipment, such as pen-and-paper or a computer mouse. This may, in turn, promote negative attitudes toward the CT paradigm, which may correlate with poorer outcomes. Consequently, optimizing a system for the delivery of CT in the PD population may improve the accessibility of and engagement with the CT paradigm, subsequently leading to better outcomes. To achieve this, the NeuroOrb Gaming System was designed, coupling a novel accessible controller, specifically developed for use with people with motor impairments, with a "Serious Games" software suite, custom-designed to target the cognitive domains typically affected in PD. The aim of the current study was to evaluate the usability of the NeuroOrb through a reiterative co-design process, in order to optimize the system for future use in clinical trials of CT in individuals with PD. Individuals with PD (n = 13; mean age = 68.15 years; mean disease duration = 8 years) were recruited from the community and participated in three co-design loops. After implementation of key stakeholder feedback to make significant modifications to the system, system usability was improved and participant attitudes toward the NeuroOrb were very positive. Taken together, this provides rationale for moving forward with a future clinical trial investigating the utility of the NeuroOrb as a tool to deliver CT in PD.

Characterizing the Dynamic Disassembly/Reassembly Mechanisms of Encapsulin Protein Nanocages.

Encapsulins, self-assembling icosahedral protein nanocages derived from prokaryotes, represent a versatile set of tools for nanobiotechnology. However, a comprehensive understanding of the mechanisms underlying encapsulin self-assembly, disassembly, and reassembly is lacking. Here, we characterize the disassembly/reassembly properties of three encapsulin nanocages that possess different structural architectures: T = 1 (24 nm), T = 3 (32 nm), and T = 4 (42 nm). Using spectroscopic techniques and electron microscopy, encapsulin architectures were found to exhibit varying sensitivities to the denaturant guanidine hydrochloride (GuHCl), extreme pH, and elevated temperature. While all three encapsulins showed the capacity to reassemble following GuHCl-induced disassembly (within 75 min), only the smallest T = 1 nanocage reassembled after disassembly in basic pH (within 15 min). Furthermore, atomic force microscopy revealed that all encapsulins showed a significant loss of structural integrity after undergoing sequential disassembly/reassembly steps. These findings provide insights into encapsulins' disassembly/reassembly dynamics, thus informing their future design, modification, and application.

Impact of "chemobrain" in childhood cancer survivors on social, academic, and daily living skills: a qualitative systematic review protocol.

OBJECTIVE: The objective of this review is to examine children's experiences of chemotherapy-induced cognitive impairment (also known as "chemobrain") and the impact of chemobrain on children's social, academic, and daily living skills. INTRODUCTION: The effect of childhood chemotherapy treatment on cognition is of concern because of the vulnerable nature of children's developing brains and the potential to cause lifelong detriments socially, academically, and economically. Furthermore, this population is under-represented in the chemobrain literature and in survivorship care plans. As cancer survivorship among this group increases, it is important to understand childhood experiences so that rehabilitation strategies and suitable supports can be put in place. INCLUSION CRITERIA: This review of qualitative studies will focus on the pediatric population (0 to 18 years of age) during and/or following chemotherapy treatment to identify their experiences with chemobrain. The review will include any studies using a qualitative research methodology (eg, surveys, focus groups, interview transcripts), conducted in any geographic location, where experiences are presented from the child's perspective. Studies assessing children's experiences of cancer, other chemotherapy-related side effects, or the parent's personal experience will be excluded. METHODS: A search of MEDLINE, Embase, PsycINFO, and CINAHL databases will be conducted. Full-text, English-only articles employing a qualitative research methodology will be included in the screening process. Two independent reviewers will retrieve and screen full-text studies, and assess methodological quality of the included studies. Meta-aggregation will be performed and a ConQual Summary of Findings will present the confidence in the findings. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42021240573.

Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?

Ischaemic stroke involves the rapid onset of focal neurological dysfunction, most commonly due to an arterial blockage in a specific region of the brain. Stroke is a leading cause of death and common cause of disability, with over 17 million people worldwide suffering from a stroke each year. It is now well-documented that neuroinflammation and immune mediators play a key role in acute and long-term neuronal tissue damage and healing, not only in the infarct core but also in distal regions. Importantly, in these distal regions, termed sites of secondary neurodegeneration (SND), spikes in neuroinflammation may be seen sometime after the initial stroke onset, but prior to the presence of the neuronal tissue damage within these regions. However, it is key to acknowledge that, despite the mounting information describing neuroinflammation following ischaemic stroke, the exact mechanisms whereby inflammatory cells and their mediators drive stroke-induced neuroinflammation are still not fully understood. As a result, current anti-inflammatory treatments have failed to show efficacy in clinical trials. In this review we discuss the complexities of post-stroke neuroinflammation, specifically how it affects neuronal tissue and post-stroke outcome acutely, chronically, and in sites of SND. We then discuss current and previously assessed anti-inflammatory therapies, with a particular focus on how failed anti-inflammatories may be repurposed to target SND-associated neuroinflammation.

Optimizing Cognitive Training for the Treatment of Cognitive Dysfunction in Parkinson's Disease: Current Limitations and Future Directions.

Cognitive dysfunction, primarily involving impairments in executive function, visuospatial function and memory, is one of the most common non-motor symptoms of Parkinson's disease (PD). Currently, the only pharmacological treatments available for the treatment of cognitive dysfunction in PD provide variable benefit, making the search for potential non-pharmacological therapies to improve cognitive function of significant interest. One such therapeutic strategy may be cognitive training (CT), which involves the repetition of standardized tasks with the aim of improving specific aspects of cognition. Several studies have examined the effects of CT in individuals with PD and have shown benefits in a variety of cognitive domains, but the widespread use of CT in these individuals may be limited by motor impairments and other concerns in study design. Here, we discuss the current state of the literature on the use of CT for PD and propose recommendations for future implementation. We also explore the potential use of more recent integrative, adaptive and assistive technologies, such as virtual reality, which may optimize the delivery of CT in PD.

The potential role of glial cells in driving the prion-like transcellular propagation of tau in tauopathies.

Dementia is one of the leading causes of death worldwide, with tauopathies, a class of diseases defined by pathology associated with the microtubule-enriched protein, tau, as the major contributor. Although tauopathies, such as Alzheimer's disease and Frontotemporal dementia, are common amongst the ageing population, current effective treatment options are scarce, primarily due to the incomplete understanding of disease pathogenesis. The mechanisms via which aggregated forms of tau are able to propagate from one anatomical area to another to cause disease spread and progression is yet unknown. The prion-like hypothesis of tau propagation proposes that tau can propagate along neighbouring anatomical areas in a similar manner to prion proteins in prion diseases, such as Creutzfeldt-Jacob disease. This hypothesis has been supported by a plethora of studies that note the ability of tau to be actively secreted by neurons, propagated and internalised by neighbouring neuronal cells, causing disease spread. Surfacing research suggests a role of reactive astrocytes and microglia in early pre-clinical stages of tauopathy through their inflammatory actions. Furthermore, both glial types are able to internalise and secrete tau from the extracellular space, suggesting a potential role in tau propagation; although understanding the physiological mechanisms by which this can occur remains poorly understood. This review will discuss the current literature around the prion-like propagation of tau, with particular emphasis on glial-mediated neuroinflammation and the contribution it may play in this propagation process.

Fyn Kinase Activity and Its Role in Neurodegenerative Disease Pathology: a Potential Universal Target?

Fyn is a non-receptor tyrosine kinase belonging to the Src family of kinases (SFKs) which has been implicated in several integral functions throughout the central nervous system (CNS), including myelination and synaptic transmission. More recently, Fyn dysfunction has been associated with pathological processes observed in neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD) and Parkinson's disease (PD). Neurodegenerative diseases are amongst the leading cause of death and disability worldwide and, due to the ageing population, prevalence is predicted to rise in the coming years. Symptoms across neurodegenerative diseases are both debilitating and degenerative in nature and, concerningly, there are currently no disease-modifying therapies to prevent their progression. As such, it is important to identify potential new therapeutic targets. This review will outline the role of Fyn in normal/homeostatic processes, as well as degenerative/pathological mechanisms associated with neurodegenerative diseases, such as demyelination, pathological protein aggregation, neuroinflammation and cognitive dysfunction.

More than motor impairment: A spatiotemporal analysis of cognitive impairment and associated neuropathological changes following cortical photothrombotic stroke.

There is emerging evidence suggesting that a cortical stroke can cause delayed and remote hippocampal dysregulation, leading to cognitive impairment. In this study, we aimed to investigate motor and cognitive outcomes after experimental stroke, and their association with secondary neurodegenerative processes. Specifically, we used a photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Motor function was assessed using the cylinder and grid walk tasks. Changes in cognition were assessed using a mouse touchscreen platform. Neuronal loss, gliosis and amyloid-ß accumulation were investigated in the peri-infarct and ipsilateral hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed persistent impairment in cognitive function post-stroke, whilst there was a modest spontaneous motor recovery over the investigated period of 84 days. In the peri-infarct region, we detected a reduction in neuronal loss and decreased neuroinflammation over time post-stroke, which potentially explains the spontaneous motor recovery. Conversely, we observed persistent neuronal loss together with concomitant increased neuroinflammation and amyloid-ß accumulation in the hippocampus, which likely accounts for the persistent cognitive dysfunction. Our findings indicate that cortical stroke induces secondary neurodegenerative processes in the hippocampus, a region remote from the primary infarct, potentially contributing to the progression of post-stroke cognitive impairment.

Neurotoxin-Induced Rodent Models of Parkinson's Disease: Benefits and Drawbacks.

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by cardinal motor impairments, including akinesia and tremor, as well as by a host of non-motor symptoms, including both autonomic and cognitive dysfunction. PD is associated with a death of nigral dopaminergic neurons, as well as the pathological spread of Lewy bodies, consisting predominantly of the misfolded protein alpha-synuclein. To date, only symptomatic treatments, such as levodopa, are available, and trials aiming to cure the disease, or at least halt its progression, have not been successful. Wong et al. (2019) suggested that the lack of effective therapy against neurodegeneration in PD might be attributed to the fact that the molecular mechanisms standing behind the dopaminergic neuronal vulnerability are still a major scientific challenge. Understanding these molecular mechanisms is critical for developing effective therapy. Thirty-five years ago, Calne and William Langston (1983) raised the question of whether biological or environmental factors precipitate the development of PD. In spite of great advances in technology and medicine, this question still lacks a clear answer. Only 5-15% of PD cases are attributed to a genetic mutation, with the majority of cases classified as idiopathic, which could be linked to exposure to environmental contaminants. Rodent models play a crucial role in understanding the risk factors and pathogenesis of PD. Additionally, well-validated rodent models are critical for driving the preclinical development of clinically translatable treatment options. In this review, we discuss the mechanisms, similarities and differences, as well as advantages and limitations of different neurotoxin-induced rat models of PD. In the second part of this review, we will discuss the potential future of neurotoxin-induced models of PD. Finally, we will briefly demonstrate the crucial role of gene-environment interactions in PD and discuss fusion or dual PD models. We argue that these models have the potential to significantly further our understanding of PD.