Secondary Neurodegeneration Research Articles

Intranasal Administration of Chitosan-Nanoparticles Conjugated with Imipramine and its Effect on Stroke-Induced Secondary Neurodegeneration: A Research Protocol

Introduction: Stroke is the second leading cause of death and the third leading cause of permanent disability worldwide. Notably, the recovery period post-stroke is crucial as there is a risk of stroke-induced secondary neurodegeneration. Stroke-induced secondary neurodegeneration is the inevitable loss of viable brain tissue at sites distal from the initial infarct. It shares similarities with neurodegenerative diseases and results in neurological deficits, further complicating stroke recovery. Intranasal administration of chitosan-nanoparticles conjugated with imipramine will be tested to determine if they elicit a synergistic effect in mitigating disease processes associated with stroke-induced secondary neurodegeneration. Methods: Treatment and testing will be conducted in 30 male Wistar rats aged 12 months. Stroke will be induced by occluding the middle cerebral artery. Rats will be divided into three groups of 10 and will receive an intranasal dose of either saline (Control, C), 20mg/kg of imipramine (Treatment 1, T1), or 20mg/kg of chitosan-nanoparticles conjugated with imipramine (Treatment 2, T2). Statistical analysis using analysis of variance will determine if chitosan-nanoparticles conjugated with imipramine can mitigate the effects of stroke-induced secondary neurodegeneration determined by the proposed tests. Results: T2 given 20mg/kg of chitosan-nanoparticles conjugated with imipramine is proposed to spend more time exploring the unfamiliar object in the novel object recognition test. Lesser evidence of Alzheimer’s disease in T2 is expected, as measured by the fludeoxyglucose positron emission tomography imaging. A higher serum brain-derived neurotrophic factor measured by an enzyme-linked immunosorbent assay is also expected to be present in T2. Discussion: It is anticipated that chitosan-nanoparticles conjugated with imipramine will exhibit a synergistic effect in mitigating disease processes accompanying stroke-induced secondary neurodegeneration because of properties associated with neuroplasticity and enhanced drug targeting efficacy. Conclusion: This research protocol aims to elucidate a novel treatment that can be applied to stroke recovery to mitigate stroke-induced secondary neurodegeneration, which tends to complicate this crucial period. Our proposal could have implications in the prognosis and management of stroke and post-stroke recovery, respectively, and inspire a framework for the discovery of novel post-stroke therapeutic interventions.

A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis.

Multiple sclerosis (MS) lesions that do not resolve in the months after they form harbour ongoing demyelination and axon degeneration, and are identifiable in vivo by their paramagnetic rims on MRI scans1-3. Here, to define mechanisms underlying this disabling, progressive neurodegenerative state4-6 and foster development of new therapeutic agents, we used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation. We uncovered notable glial and immune cell diversity, especially at the chronically inflamed lesion edge. We define 'microglia inflamed in MS' (MIMS) and 'astrocytes inflamed in MS', glial phenotypes that demonstrate neurodegenerative programming. The MIMS transcriptional profile overlaps with that of microglia in other neurodegenerative diseases, suggesting that primary and secondary neurodegeneration share common mechanisms and could benefit from similar therapeutic approaches. We identify complement component 1q (C1q) as a critical mediator of MIMS activation, validated immunohistochemically in MS tissue, genetically by microglia-specific C1q ablation in mice with experimental autoimmune encephalomyelitis, and therapeutically by treating chronic experimental autoimmune encephalomyelitis with C1q blockade. C1q inhibition is a potential therapeutic avenue to address chronic white matter inflammation, which could be monitored by longitudinal assessment of its dynamic biomarker, paramagnetic rim lesions, using advanced MRI methods.

Complement component 3 from astrocytes mediates retinal ganglion cell loss during neuroinflammation.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by varying degrees of secondary neurodegeneration. Retinal ganglion cells (RGC) are lost in MS in association with optic neuritis but the mechanisms of neuronal injury remain unclear. Complement component C3 has been implicated in retinal and cerebral synaptic pathology that may precede neurodegeneration. Herein, we examined post-mortem MS retinas, and then used a mouse model, experimental autoimmune encephalomyelitis (EAE), to examine the role of C3 in the pathogenesis of RGC loss associated with optic neuritis. First, we show extensive C3 expression in astrocytes (C3+/GFAP+ cells) and significant RGC loss (RBPMS+ cells) in post-mortem retinas from people with MS compared to retinas from non-MS individuals. A patient with progressive MS with a remote history of optic neuritis showed marked reactive astrogliosis with C3 expression in the inner retina extending into deeper layers in the affected eye more than the unaffected eye. To study whether C3 mediates retinal degeneration, we utilized global C3-/- EAE mice and found that they had less RGC loss and partially preserved neurites in the retina compared with C3+/+ EAE mice. C3-/- EAE mice had fewer axonal swellings in the optic nerve, reflecting reduced axonal injury, but had no changes in demyelination or T cell infiltration into the CNS. Using a C3-tdTomato reporter mouse line, we show definitive evidence of C3 expression in astrocytes in the retina and optic nerves of EAE mice. Conditional deletion of C3 in astrocytes showed RGC protection replicating the effects seen in the global knockouts. These data implicate astrocyte C3 expression as a critical mediator of retinal neuronal pathology in EAE and MS, and are consistent with recent studies showing C3 gene variants are associated with faster rates of retinal neurodegeneration in human disease.

White matter degeneration revealed by fiber-specific analysis relates to recovery of hand function after stroke.

Recent developments of higher‐order diffusion‐weighted imaging models have enabled the estimation of specific white matter fiber populations within a voxel, addressing limitations of traditional imaging markers of white matter integrity. We applied fixel based analysis (FBA) to investigate the evolution of fiber‐specific white matter changes in a prospective study of stroke patients and upper limb motor deficit over 1 year after stroke. We studied differences in fiber density and macrostructural changes in fiber cross‐section. Motor function was assessed by grip strength. We conducted a whole‐brain analysis of fixel metrics and predefined corticospinal tract (CST) region of interest in relation to changes in motor functions. In 30 stroke patients (mean age 62.3 years, SD ±16.9; median NIHSS 4, IQR 2–5), whole‐brain FBA revealed progressing loss of fiber density and cross‐section in the ipsilesional corticospinal tract and long‐range fiber tracts such as the superior longitudinal fascicle and trans‐callosal tracts extending towards contralesional white matter tracts. Lower FBA metrics measured at the brainstem section of the CST 1 month after stroke were significantly associated with lower grip strength 3 months (p = .009, adjusted R 2 = 0.259) and 1 year (T4: p < .001, adj. R 2 = 0.515) after stroke. Compared to FA, FBA metrics showed a comparably strong association with grip strength at later time points. Using FBA, we demonstrate progressive fiber‐specific white matter loss after stroke and association with functional motor outcome. Our results promote the application of fiber‐specific analysis to detect secondary neurodegeneration after stroke in relation to clinical recovery.

Multicenter Prospective Analysis of Hypertrophic Olivary Degeneration Following Infratentorial Stroke (HOD-IS): Evaluation of Disease Epidemiology, Clinical Presentation, and MR-Imaging Aspects

Introduction: Ischemic and hemorrhagic strokes in the brainstem and cerebellum with injury to the functional loop of the Guillain-Mollaret triangle (GMT) can trigger a series of events that result in secondary trans-synaptic neurodegeneration of the inferior olivary nucleus. In an unknown percentage of patients, this leads to a condition called hypertrophic olivary degeneration (HOD). Characteristic clinical symptoms of HOD progress slowly over months and consist of a rhythmic palatal tremor, vertical pendular nystagmus, and Holmes tremor of the upper limbs. Diffusion Tensor Imaging (DTI) with tractography is a promising method to identify functional pathway lesions along the cerebello-thalamo-cortical connectivity and to generate a deeper understanding of the HOD pathophysiology. The incidence of HOD development following stroke and the timeline of clinical symptoms have not yet been determined in prospective studies—a prerequisite for the surveillance of patients at risk.Methods and Analysis: Patients with ischemic and hemorrhagic strokes in the brainstem and cerebellum with a topo-anatomical relation to the GMT are recruited within certified stroke units of the Interdisciplinary Neurovascular Network of the Rhine-Main. Matching lesions are identified using a predefined MRI template. Eligible patients are prospectively followed up and present at 4 and 8 months after the index event. During study visits, a clinical neurological examination and brain MRI, including high-resolution T2-, proton-density-weighted imaging, and DTI tractography, are performed. Fiberoptic endoscopic evaluation of swallowing is optional if palatal tremor is encountered.Study Outcomes: The primary endpoint of this prospective clinical multicenter study is to determine the frequency of radiological HOD development in patients with a posterior fossa stroke affecting the GMT at 8 months after the index event. Secondary endpoints are identification of (1) the timeline and relevance of clinical symptoms, (2) lesion localizations more prone to HOD occurrence, and (3) the best MR-imaging regimen for HOD identification. Additionally, (4) DTI tractography data are used to analyze individual pathway lesions. The aim is to contribute to the epidemiological and pathophysiological understanding of HOD and hereby facilitate future research on therapeutic and prophylactic measures.Clinical Trial Registration: HOD-IS is a registered trial at https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00020549.

Is Cerebral Amyloid-β Deposition Related to Post-stroke Cognitive Impairment?

Approximately two-thirds of ischemic stroke patients suffer from different levels of post-stroke cognitive impairment (PSCI),but the underlying mechanisms of PSCI remain unclear. Cerebral amyloid-β (Aβ) deposition, a pathological hallmark of Alzheimer's disease, has been discovered in the brains of stroke patients in some autopsy studies. However, less is known aboutthe role of Aβ pathology in the development ofPSCI. It is hypothesized that cerebral ischemic injury may lead to neurotoxic Aβ accumulation in the brain, which further induces secondary neurodegeneration and progressive cognitive decline after stroke onset. In this review, we summarized available evidence from pre-clinical and clinical studies relevant to the aforementioned hypothesis. We found inconsistency in the results obtained from studies in rodents, nonhuman primates, and stroke patients. Moreover, the causal relationship between post-stroke cerebral Aβ deposition and PSCI has been uncertain and controversial. Taken together, evidence supporting the hypothesis that brain ischemia induces cerebral Aβ deposition has been insufficient so far. And, there is still no consensus regarding the contribution of cerebralamyloid pathology to PSCI. Other non-amyloid neurodegenerative mechanisms might be involved and remain to befully elucidated.

Neurofilament Light Chain (NfL) in Blood-A Biomarker Predicting Unfavourable Outcome in the Acute Phase and Improvement in the Late Phase after Stroke.

Increased sensitivity of methods assessing the levels of neurofilament light chain (NfL), a neuron-specific intermediate filament protein, in human plasma or serum, has in recent years led to a number of studies addressing the utility of monitoring NfL in the blood of stroke patients. In this review, we discuss that elevated blood NfL levels after stroke may reflect several different neurobiological processes. In the acute and post-acute phase after stroke, high blood levels of NfL are associated with poor clinical outcome, and later on, the blood levels of NfL positively correlate with secondary neurodegeneration as assessed by MRI. Interestingly, increased blood levels of NfL in individuals who survived stroke for more than 10 months were shown to predict functional improvement in the late phase after stroke. Whereas in the acute phase after stroke the injured axons are assumed to be the main source of blood NfL, synaptic turnover and secondary neurodegeneration could be major contributors to blood NfL levels in the late phase after stroke. Elevated blood NfL levels after stroke should therefore be interpreted with caution. More studies addressing the clinical utility of blood NfL assessment in stroke patients are needed before the inclusion of NfL in the clinical workout as a useful biomarker in both the acute and the chronic phase after stroke.

Protective effects of Da-cheng-qi decoction in rats with intracerebral hemorrhage

BackgroundIntracerebral hemorrhage (ICH), the most fatal subtype of stroke, has no disease-modifying treatment. Da-cheng-qi decoction (DCQ), composed of rhubarb, is one of the most commonly used Chinese traditional decoctions in ICH treatment. But the mechanism is not clear. Emodin is an active compound found in rhubarb. PurposeTo study the protective effects of DCQ on ICH and its possible mechanisms of action. MethodsThe ICH model was reproduced by injecting collagenase-VII into the left caudate putamen (CPu) of rats. DCQ and emodin were used to treat the ICH rats for 7 days. Behavior tests, proteomic analysis, morphological studies, and western blotting were performed. ResultsThe neurological deficits in the ICH rats recovered with DCQ and emodin on the 14th day after ICH. The proteomics data revealed that DCQ significantly corrected the pathological signals in the CPu and hippocampus after ICH. The numbers of amoebic microglia in the CPu and M2 microglia in both CPu and hippocampus were significantly increased after DCQ and emodin treatment. The increase in GluN2B-containing NMDA receptor (NR2B) and postsynaptic density protein-95, activation of mitogen-activated protein kinase (MAPK) signals in the CPu, and secondary neurodegeneration (SND) in the hippocampus were significantly recovered in DCQ-treated rats. Inhibition of MAPK p38 (p38) in the hippocampus was observed after DCQ and emodin treatment. ConclusionThe protective effects of DCQ on ICH were confirmed in this study, and its mechanism may be related to the inhibition of MAPK and activation of M2 microglia. These results are beneficial to the development of ICH therapeutic targets.

Plasma neurofilament light chain levels predict improvement in late phase after stroke

Although functional recovery is most pronounced in the first 6months after stroke, improvement is possible also in the late phase. The value of plasma neurofilament light chain (NfL), a biomarker of axonal injury and secondary neurodegeneration, was explored for the prediction of functional improvement in the late phase after stroke. Baseline plasma NfL levels were measured in 115 participants of a trial on the efficacy of multimodal rehabilitation in the late phase after stroke. The association between NfL levels, impairment in balance, gait and cognitive domains, and improvement 3 and 9months later was determined. Plasma NfL levels were associated with the degree of impairment in all three domains. Individuals with meaningful improvement in balance and gait capacity had higher plasma NfL levels compared with non-improvers (p=0.001 and p=0.018, respectively). Higher NfL levels were associated with improvement in balance (odds ratio [OR] 2.34, 95% confidence interval [CI] 1.35-4.27, p=0.004) and gait (OR 2.27, 95% CI 1.25-4.32, p=0.009). Elevated plasma NfL levels showed a positive predictive value for cognitive improvement, and this effect was specific for the intervention targeting the cognitive domain. The association of NfL levels with cognitive improvement withstood correction for baseline impairment, age and total years of schooling (OR 7.54, 95% CI 1.52-45.66, p=0.018). In addition to its established role as a biomarker in the acute phase, elevated circulating NfL levels may predict functional improvement in the late phase after stroke. Our results should prompt further studies into the use of plasma NfL as a biomarker in the late phase after stroke.

Pathogenic Functions of Tumor Necrosis Factor Receptor-Associated Factor 6 Signaling Following Traumatic Brain Injury.

Neuroinflammation contributes to delayed (secondary) neurodegeneration following traumatic brain injury (TBI). Tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling may promote post-TBI neuroinflammation, thereby exacerbating secondary injury. This study investigated the pathogenic functions of TRAF6 signaling following TBI in vivo and in vitro. A rat TBI model was established by air pressure contusion while lipopolysaccharide (LPS) exposure was used to induce inflammatory-like responses in cultured astrocytes. Model rats were examined for cell-specific expression of TRAF6, NF-κB, phosphorylated (p)-NF-κB, MAPKs (ERK, JNK, and p38), p-MAPKs, chemokines (CCL2 and CXCL1), and chemokine receptors (CCR2 and CXCR2) by immunofluorescence, RT-qPCR, western blotting, and ELISA, for apoptosis by TUNEL staining, and spatial cognition by Morris water maze testing. These measurements were compared between TBI model rats receiving intracerebral injections of TRAF6-targeted RNAi vector (AAV9-TRAF6-RNAi), empty vector, MAPK/NF-κB inhibitors, or vehicle. Primary astrocytes were stimulated with LPS following TRAF6 siRNA or control transfection, and NF-κB, MAPKs, chemokine, and chemokine receptor expression levels evaluated by western blotting and ELISA. TRAF6 was expressed mainly in astrocytes and neurons of injured cortex, peaking 3 days post-TBI. Knockdown by AAV9-TRAF6-RNAi improved spatial learning and memory, decreased TUNEL-positive cell number in injured cortex, and downregulated expression levels of p-NF-κB, p-ERK, p-JNK, p-p38, CCL2, CCR2, CXCL1, and CXCR2 post-TBI. Inhibitors of NF-κB, ERK, JNK, and p38 significantly suppressed CCL2, CCR2, CXCL1, and CXCR2 expression following TBI. Furthermore, TRAF6-siRNA inhibited LPS-induced NF-κB, ERK, JNK, p38, CCL2, and CXCL1 upregulation in cultured astrocytes. Targeting TRAF6-MAPKs/NF-κB-chemokine signaling pathways may provide a novel therapeutic approach for reducing post-TBI neuroinflammation and concomitant secondary injury.

Secondary Neurodegeneration: A General Approach to Axonal and Transaxonal Degeneration

CNS WM tracts are mainly composed of axons, and when these structures undergo apoptosis or lose their integrity, neurodegeneration may occur. Secondary neuronal degeneration can be classified as axonal degeneration and involves only the first neuron in a pathway (Wallerian degeneration of the corticospinal tract being its prototype) or be classified as transaxonal degeneration and involve more than a single neuron in a common pathway, usually a closed neuronal circuit, in specific tracts, such as the dentate-rubro-olivary tract, tracts of the limbic system, corticopontocerebellar tract, cranial nerve tracts, and nigrostriatal pathway. This study aimed to review the anatomy of the main CNS tracts susceptible to secondary neuronal degeneration and to illustrate, through different imaging modalities, the findings associated with this poorly explored and understood process involved in the pathophysiologic substrate of numerous neurologic diseases.Learning Objective: Recognize the anatomy of the main CNS tracts susceptible to secondary neuronal degeneration and identify its main imaging findings in different imaging modalities.

Thalamic Injury and Cognition in Multiple Sclerosis.

Multiple sclerosis (MS) produces demyelination and degeneration in both gray and white matter. Both cortical and deep gray matter injury is observed during the course of MS. Among deep gray matter structures, the thalamus has received special attention, as it undergoes volume loss in different MS subtypes and is involved in the earliest form of the disease, radiologically isolated syndrome. The thalamus plays an important role as an information relay center, and involvement of the thalamus in MS has been associated with a variety of clinical manifestations in MS, including fatigue, movement disorders, pain, and cognitive impairment (CI). Similar to thalamic volume loss, CI is seen from the earliest stages of MS and is potentially one of the most debilitating manifestations of the disease. The thalamus, particularly the dorsomedial nucleus as part of the basolateral limbic circuit and anterior thalamic nuclei through connections with the prefrontal cortex, has been shown to be involved in CI. Specifically, several cognitive performance measures such as processing speed and memory correlate with thalamic volume. Thalamic atrophy is one of the most important predictors of CI in MS, and both thalamic volume, diffusion tensor imaging measures, and functional activation correlate with the degree of CI in MS. Although the exact mechanism of thalamic atrophy is not well-understood, it is hypothesized to be secondary to degeneration following white matter injury resulting in secondary neurodegeneration and neuronal loss. The thalamus may represent an ideal biomarker for studies aiming to test neuroprotective or restorative therapies aimed at cognition.

Linking cortical atrophy to white matter hyperintensities of presumed vascular origin

We examined the relationship between white matter hyperintensities (WMH) and cortical neurodegeneration in cerebral small vessel disease (CSVD) by investigating whether cortical thickness is a remote effect of WMH through structural fiber tract connectivity in a population at increased risk of CSVD. We measured cortical thickness on T1-weighted images and segmented WMH on FLAIR images in 930 participants of a population-based cohort study at baseline. DWI-derived whole-brain probabilistic tractography was used to define WMH connectivity to cortical regions. Linear mixed-effects models were applied to analyze the relationship between cortical thickness and connectivity to WMH. Factors associated with cortical thickness (age, sex, hemisphere, region, individual differences in cortical thickness) were added as covariates. Median age was 64 [IQR 46–76] years. Visual inspection of surface maps revealed distinct connectivity patterns of cortical regions to WMH. WMH connectivity to the cortex was associated with reduced cortical thickness (p = 0.009) after controlling for covariates. This association was found for periventricular WMH (p = 0.001) only. Our results indicate an association between WMH and cortical thickness via connecting fiber tracts. The results imply a mechanism of secondary neurodegeneration in cortical regions distant, yet connected to subcortical vascular lesions, which appears to be driven by periventricular WMH.

Lifestyle and Mediterranean diet adherence in a cohort of Southern Italian patients with Multiple Sclerosis

Background/objectivesSeveral studies supported the beneficial effects of the Mediterranean diet (MeDi) on chronic diseases. In Multiple Sclerosis (MS), the MeDi might interfere with systemic inflammatory state, gut microbiota, and comorbidities. The Med Diet Score (MDS) estimates the adherence to the MeDi and the cardiovascular (CV) risk. Aims of our study were i) to photograph lifestyle and diet habits of a southern Italy cohort of people with MS (pwMS), and ii) to investigate the impact of the MeDi on MS clinical outcomes. Subjects/methodsWe conducted a multi-center, cross-sectional study, enrolling 435 consecutive consenting pwMS, attending the outpatient clinics for routine follow-up visits. Participants underwent a clinical examination and a 29-item self-administered questionnaire on life and dietary habits. Disease phenotype, Expanded Disability Status Scale (EDSS), MS Severity Score (MSSS), waist circumference (WC), Body Mass Index (BMI), therapies, and comorbidities, were updated. MDS was assessed and correlated with current and retrospective clinical data. Results75.8% of respondents were interested in nutrition, 72.8% were non-smokers, 52.9% performed physical activity, and 45.6% used food supplements. MDS was higher in pwMS with normal WC (p = 0.031), and inversely correlated with MSSS (p = 0.013) and EDSS (p = 0.012) at survey time. MDS did not correlate with the total number of relapses (before and after diagnosis) (p = 0.372). Metabolic comorbidities were associated with an increased 10-year CV risk (r = 0.85, p = 0.002). ConclusionOur findings suggest a putative beneficial effect of the MeDi on WC, MS course and disability. Given the role of chronic systemic inflammation in maintenance of autoimmunity and secondary neurodegeneration, both involved in long-term disability, we may suppose a beneficial effect of the MeDi on MS long-term disability outcomes, probably mediated by a modulation of the gut microbiota and the low-grade chronic systemic inflammation.

Stroke promotes the development of brain atrophy and delayed cell death in hypertensive rats

Post-stroke cognitive impairment (PSCI) is a major source of disability, affecting up to two thirds of stroke survivors with no available therapeutic options. The condition remains understudied in preclinical models due to its delayed presentation. Although hypertension is a leading risk factor for dementia, how ischemic stroke contributes to this neurodegenerative condition is unknown. In this study, we used a model of hypertension to study the development of PSCI and its mechanisms. Spontaneously hypertensive rats (SHR) were compared to normotensive rats and were subjected to 1-h middle cerebral artery occlusion or sham surgery. Novel object recognition, passive avoidance test and Morris water maze were used to assess cognition. In addition, brain magnetic resonance images were obtained 12-weeks post-stroke and tissue was collected for immunohistochemistry and protein quantification. Stroked animals developed impairment in long-term memory at 4-weeks post-stroke despite recovery from motor deficits, with hypertensive animals showing some symptoms of anhedonia. Stroked SHRs displayed grey matter atrophy and had a two-fold increase in apoptosis in the ischemic borderzone and increased markers of inflammatory cell death and DNA damage at 12 weeks post-stroke. This indicates that preexisting hypertension exacerbates the development of secondary neurodegeneration after stroke beyond its acute effects on neurovascular injury.

Neuroinflammation Mechanisms and Phytotherapeutic Intervention: A Systematic Review.

Neuroinflammation is indicated in the pathogenesis of several acute and chronic neurological disorders. Acute lesions in the brain parenchyma induce intense and highly complex neuroinflammatory reactions with similar mechanisms among various disease prototypes. Microglial cells in the CNS sense tissue damage and initiate inflammatory responses. The cellular and humoral constituents of the neuroinflammatory reaction to brain injury contribute significantly to secondary brain damage and neurodegeneration. Inflammatory cascades such as proinflammatory cytokines from invading leukocytes and direct cell-mediated cytotoxicity between lymphocytes and neurons are known to cause "collateral damage" in models of acute brain injury. In addition to degeneration and neuronal cell loss, there are secondary inflammatory mechanisms that modulate neuronal activity and affect neuroinflammation which can even be detected at the behavioral level. Hence, several of health conditions result from these pathogenetic conditions which are underlined by progressive neuronal function loss due to chronic inflammation and oxidative stress. In the first part of this Review, we discuss critical neuroinflammatory mediators and their pathways in detail. In the second part, we review the phytochemicals which are considered as potential therapeutic molecules for treating neurodegenerative diseases with an inflammatory component.

Commentary on Some Recent Theses Relevant to Combating Aging: August 2020.

Theses reviewed in this issue include "Characterization and Purification of Putative Stem Cells from the Adult Murine Pancreas," "Inhibition of TLR4 Minimizes Islet Damage due to Sterile Inflammation and Improves Islet Transplant Outcomes," "Liquefaction of the Brain Following Stroke Shares Multiple Characteristics with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism," "Manipulating the Segregation of Human Mitochondrial DNA," "Role of Mitochondria in Plasma Membrane Repair and Pathogenesis of Muscular Dystrophy," and "The Role of Cytosolic Accumulation of Nuclear DNA in Retinal-Pigment Epithelium Dysfunction and Age-Related Macular Degeneration."

Altered circular RNA expression profiles in the non-ischemic thalamus in focal cortical infarction mice.

Focal cerebral infarction leads to secondary changes in non-ischemic areas remote from but connected to the infarct site. Circular RNAs (circRNAs) are involved in the pathophysiological processes of many diseases. However, the expression and roles of circRNAs in non-ischemic remote regions after ischemic stroke remain unknown. In this study, adult male C57BL/6J mice were subjected to permanent distal middle cerebral artery occlusion (MCAO) to establish focal cortical infarction. High-throughput sequencing was used to profile the circRNA expression in the mouse ipsilateral thalamus at 7 and 14 d after MCAO. Bioinformatics analyses were conducted to predict the function of the differential expressed circRNAs’ host and target genes. Compared with sham group, a total of 2659 circRNAs were significantly altered in the ipsilateral thalamus at 7 or 14 d after MCAO in mice. Among them, 73 circRNAs were significantly altered at both two time points after stroke. GO and KEGG analyses indicated that circRNAs plays important roles in secondary thalamic neurodegeneration and remodeling after focal cortical infarction. This is the first study to profile the circRNA expression in non-ischemic region of ischemic stroke, suggesting that circRNAs may be therapeutic targets for reducing post-stroke secondary remote neurodegeneration.

Advances in Studies on Stroke-Induced Secondary Neurodegeneration (SND) and Its Treatment.

The occurrence of secondary neurodegeneration has exclusively been observed after the first incidence of stroke. In humans and rodents, post-stroke secondary neurodegeneration (SND) is an inevitable event that can lead to progressive neuronal loss at a region distant to initial infarct. SND can lead to cognitive and motor function impairment, finally causing dementia. The exact pathophysiology of the event is yet to be explored. It is seen that the thalami, in particular, are susceptible to cause SND. The reason behind this is because the thalamus functioning as the relay center and is positioned as an interlocked structure with direct synaptic signaling connection with the cortex. As SND proceeds, accumulation of misfolded proteins and microglial activation are seen in the thalamus. This leads to increased neuronal loss and worsening of functional and cognitive impairment. There is a necessity of specific interventions to prevent post-stroke SND, which are not properly investigated to date owing to sparsely reproducible pre-clinical and clinical data. The basis of this review is to investigate about post-stroke SND and its updated treatment approaches carefully. Our article presents a detailed survey of advances in studies on stroke-induced secondary neurodegeneration (SND) and its treatment. This article aims to put forward the pathophysiology of SND. We have also tabulated the latest treatment approaches along with different neuroimaging systems that will be helpful for future reference to explore. In this article, we have reviewed the available reports on SND pathophysiology, detection techniques, and possible treatment modalities that have not been attempted to date.

Lesion Size- and Location-Dependent Recruitment of Contralesional Thalamus and Motor Cortex Facilitates Recovery after Stroke in Mice

Brain lesions caused by cerebral ischemia or hemorrhage lead to a local breakdown of energy homeostasis followed by irreversible cell death and long-term impairment. Importantly, local brain lesions also generate remote functional and structural disturbances, which contribute to the behavioral deficit but also impact the recovery of function. While spontaneous recovery has been associated with endogenous repair mechanisms at the vascular, neural, and immune cell levels, the impact of structural plasticity on sensory-motor dysfunction and recovery thereof remains to be elucidated by longitudinal imaging in a mouse model. Here, we applied behavioral assessments, in vivo fiber tracking, and histological validation in a photothrombotic stroke mouse model. Atlas-based whole-brain structural connectivity analysis and ex vivo histology revealed secondary neurodegeneration in the ipsilesional brain areas, mostly in the dorsal sensorimotor area of the thalamus. Furthermore, we describe for the first time a lesion size-dependent increase in structural connectivity between the contralesional primary motor cortex and thalamus with the ipsilesional cortex. The involvement of the contralesional hemisphere was associated with improved functional recovery relative to lesion size. This study highlights the importance of in vivo fiber tracking and the role of the contralesional hemisphere during spontaneous functional improvement as a potential novel stroke biomarker and therapeutic targets.