subcortical white matter
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2022 ◽  
pp. 1-4
Author(s):  
Nikhil Vikas Pawar ◽  
Fatima Farid Mir

A 4-month-old, previously healthy boy presented with acute onset of prolonged, recurrent seizure activity followed by neurodevelopmental deterioration and concurrent hair shaft hypopigmentation with fragility. Initial evaluation revealed significant low serum copper and ceruloplasmin, electrical status epilepticus on electroencephalography, and generalized subcortical white matter changes with diffuse tortuosity of intracranial vessels on MRI brain. In addition, a genetic study with whole-genome sequencing demonstrated a hemizygous pathogenic variant at c.2179G>A p(Gly727Arg) on ATP7A, thereby confirming the diagnosis of Menkes disease. Symptomatic treatment with antiepileptic medications was provided along with an urgent referral to an advanced center for multidisciplinary care and copper histidine replacement therapy.


2022 ◽  
Author(s):  
Anthony Fernandez-Castaneda ◽  
Peiwen Lu ◽  
Anna C Geraghty ◽  
Eric Song ◽  
Myoung-Hwa Lee ◽  
...  

Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection, without neuroinvasion, and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.


Author(s):  
Yafeng Wang ◽  
Yiran Xu ◽  
Kai Zhou ◽  
Shan Zhang ◽  
Yong Wang ◽  
...  

Abstract Radiotherapy is an effective tool in the treatment of malignant brain tumors, but irradiation-induced late-onset toxicity remains a major problem. The purpose of this study was to investigate if genetic inhibition of autophagy has an impact on subcortical white matter development in the juvenile mouse brain after irradiation. Ten-day-old selective neural Atg7 knockout (KO) mice and wild-type (WT) littermates were subjected to a single 6-Gy dose of whole-brain irradiation and evaluated at 5 days after irradiation. Neural Atg7 deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell loss in the subcortical white matter, and Atg7 deficiency partly prevented this. There was no significant change between the KO and WT mice in the number of microglia and astrocytes in the subcortical white matter after irradiation. Transcriptome analysis showed that the GO mitochondrial gene expression pathway was significantly enriched in the differentially expressed genes between the KO and WT group after irradiation. Compared with WT mice, expression of the mitochondrial fusion protein OPA1 and phosphorylation of the mitochondrial fission protein DRP1 (P-DRP1) were dramatically decreased in KO mice under physiological conditions. The protein levels of OPA1and P-DRP1 showed no differences in WT mice between the non-irradiated group and the irradiated group but had remarkably increased levels in the KO mice after irradiation. These results indicate that inhibition of autophagy reduces irradiation-induced subcortical white matter injury not by reducing inflammation, but by increasing mitochondrial fusion and inhibiting mitochondrial fission.


2021 ◽  
Author(s):  
Shanzeh M Ahmed ◽  
Nina Fransen ◽  
Hanane Touil ◽  
Iliana Michailidou ◽  
Inge Huitinga ◽  
...  

Subpial cortical demyelination is an important component of multiple sclerosis (MS) pathology contributing to disease progression, yet mechanism(s) underlying its development remain unclear. Compartmentalized inflammation involving the meninges may drive this type of injury. Given recent findings identifying substantial white matter (WM) lesion activity in patients with progressive MS, elucidating whether and how WM lesional activity relates to meningeal inflammation and subpial cortical injury is of interest. Using post-mortem formalin-fixed paraffin-embedded tissue blocks (range, 5-72 blocks; median, 30 blocks) for each of 27 progressive MS patients, we assessed the relationship between meningeal inflammation, the extent of subpial cortical demyelination, and the state of subcortical WM lesional activity. Meningeal accumulations of T cells and B cells, but not myeloid cells, were spatially adjacent to subpial cortical lesions and greater immune-cell accumulation was associated with higher subpial lesion numbers. Patients with a higher extent of meningeal inflammation harboured a greater proportion of active and mixed (active-inactive) WM lesions, and an overall lower proportion of inactive and remyelinated WM lesions. Our findings support the involvement of meningeal lymphocytes in subpial cortical injury, and also point to a potential link between inflammatory subpial cortical demyelination and pathological mechanisms occurring in the subcortical white matter.


2021 ◽  
Author(s):  
Lina Du ◽  
Chang Liu ◽  
Panpan Wang ◽  
Shaojing Li ◽  
Shuang Yue ◽  
...  

Abstract Background: Immunoglobulin A vasculitis (IgAV) is one of the most common vasculitis in children. It is generally a self-limiting disease. Due to its systemic nature, a variety of symptoms in different organs can be observed. We report a case of IgAV characterized by several complications to improve clinicians’ understanding of the disease. Case presentation: A 4-year-old boy was admitted to a local hospital because of abdominal pain and skin rash. The skin biopsy showed leukocytoclastic vasculitis with IgA deposition, consistented with a diagnosis of IgAV. He developed clinical signs of intussusception and laparotomy was undertaken. He continued to have intermittent abdominal pain and edema in the four limbs with oliguria. Elevated pancreatic enzymes and swelling of the pancreas on abdominal ultrasound suggested a combination of pancreatitis in the child. The child subsequently developed headache, dizziness and convulsions, and head MRI showed a high signal on the left side of the cortex and subcortical white matter, and he was considered to have developed cerebral vasculitis.He underwent bronchoscopy because of respiratory distress, which which confirmed the presence of pulmonary hemorrhage. Combined pulmonary infections added to the severity and complexity of his condition. He received two courses of methylprednisolone pulse therapy combined with IVIG and aggressive anti-infective therapy, but his condition eventually deteriorated and he died. Conclusions: IgAV can involve multiple systems and various complications. There is no definitive evidence to support a single drug or multi- immunosuppressive regimen. IgAV usually runs a benign course,however, the severe cases are critical, with a high mortality rate.


Pathologia ◽  
2021 ◽  
Vol 18 (3) ◽  
pp. 295-302
Author(s):  
T. V. Shulyatnikova ◽  
V. O. Tumaskyi

Pathophysiology of sepsis-associated encephalopathy (SAE) is linked to blood-brain barrier breakdown, neuroinflammation and neurotransmitter imbalance in the brain. Astroglia, the most abundant cell population within the brain, plays the critical role in control of all kinds of homeostatic processes, thereby regulating the adaptive reactions of the brain to various challenges. Astroglia are highly heterogenous across the brain regions, therefore, damaging factors stimulate heterogenous astroglial reactivity and response in different brain regions. The aim of this study was determining immunohistochemical features of GFAP expression in various brain regions in the model of rodent experimental sepsis. Materials and methods. The experiment was performed in Wistar rats: control group of 5 sham-operated rats and the main group of 20 rats subjected to cecum ligation and puncture (CLP) procedure. The immunohistochemical study of GFAP expression in the sensorimotor cortex, subcortical white matter, hippocampal, thalamic and caudate nucleus/putamen regions was performed from 20 to 48 hours of the postoperative period. Results. Starting from the 12th hour after CLP, animals began display progressive increase in signs of periorbital exudation, piloerection, fever-/hypothermia, diarrhea, social isolation, lethargy, and respiratory impairment. In the period of 20–38 hours, 9 animals showed expressed previously listed symptoms and were euthanized (CLP-B – lethal group), 11 rats survived until 48 hours of the experiment (CLP-A – survived group). In the lethal group, starting from 20 to 38 hours after the CLP procedure, a significant (relative to control) regionally-specific dynamic increase in the level of GFAP expression was observed in the brain: in the cortex – by 465 %, in the subcortical white matter – by 198 %, in the hippocampus – by 250 %, from the 23rd hour – in the caudate nucleus/putamen by 18 %. In the thalamus, no significant changes in the level of GFAP expression were observed. In the cortex and hippocampus of survived animals, 48 h after CLP, higher values of GFAP expression were observed comparing to the group of non-survived animals. Conclusions. Under conditions of the experimental SAE, an early dynamic increase in the astroglial reactivity was observed in the cortex, hippocampus, white matter, and caudate nucleus/putamen of the brain with the most significant increase of indicators in the cortex and hippocampus, which potentially indicates relatively more vulnerable areas of the brain to damaging factors, as well as places of the most active intercellular interaction in the condition of systemic inflammation. Higher values of GFAP expression in the cortex and hippocampus of survived animals at 48 hours of the experiment, compared with indicators of non-survived group, indicate increased astroglial reactivity in these brain regions at the noted time period, accompanied by relatively more favorable clinical course of the disease.  


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Deshuang Tao ◽  
Tangwu Zhong ◽  
Wei Pang ◽  
Xiaojie li

Abstract Background Cerebral palsy (CP) is a kind of disability that influences motion, and children with CP also exhibit depression-like behaviour. Inflammation has been recognized as a contributor to CP and depression, and some studies suggest that the gut-brain axis may be a contributing factor. Our team observed that Saccharomyces boulardii (S. boulardii) could reduce the inflammatory level of rats with hyperbilirubinemia and improve abnormal behaviour. Both CP and depression are related to inflammation, and probiotics can improve depression by reducing inflammation. Therefore, we hypothesize that S. boulardii may improve the behaviour and emotions of spastic CP rats through the gut-brain axis pathway. Methods Our new rat model was produced by resecting the cortex and subcortical white matter. Seventeen-day-old CP rats were exposed to S. boulardii or vehicle control by gastric gavage for 9 days, and different behavioural domains and general conditions were tested. Inflammation was assessed by measuring the inflammatory markers IL-6 and TNF-α. Hypothalamic–pituitary–adrenal (HPA) axis activity was assessed by measuring adrenocorticotropic hormone and corticosterone in the serum. Changes in the gut microbiome were detected by 16S rRNA. Results The hemiplegic spastic CP rats we made with typical spastic paralysis exhibited depression-like behaviour. S. boulardii treatment of hemiplegic spastic CP rats improves behaviour and general conditions and significantly reduces the level of inflammation, decreases HPA axis activity, and increases gut microbiota diversity. Conclusions The model developed in this study mimics a hemiplegic spastic cerebral palsy. Damage to the cortex and subcortical white matter of 17-day-old Sprague–Dawley (SD) rats led to spastic CP-like behaviour, and the rats exhibited symptoms of depression-like behaviour. Our results indicate that S. boulardii might have potential in treating hemiplegic spastic CP rat models or as an add-on therapy via the gut-brain axis pathway.


2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Mikko T. Huuskonen ◽  
Yaoming Wang ◽  
Angeliki Maria Nikolakopoulou ◽  
Axel Montagne ◽  
Zhonghua Dai ◽  
...  

Subcortical white matter (WM) stroke accounts for 25% of all strokes and is the second leading cause of dementia. Despite such clinical importance, we still do not have an effective treatment for ischemic WM stroke, and the mechanisms of WM postischemic neuroprotection remain elusive. 3K3A-activated protein C (APC) is a signaling-selective analogue of endogenous blood protease APC that is currently in development as a neuroprotectant for ischemic stroke patients. Here, we show that 3K3A-APC protects WM tracts and oligodendrocytes from ischemic injury in the corpus callosum in middle-aged mice by activating protease-activated receptor 1 (PAR1) and PAR3. We show that PAR1 and PAR3 were also required for 3K3A-APC’s suppression of post–WM stroke microglia and astrocyte responses and overall improvement in neuropathologic and functional outcomes. Our data provide new insights into the neuroprotective APC pathway in the WM and illustrate 3K3A-APC’s potential for treating WM stroke in humans, possibly including multiple WM strokes that result in vascular dementia.


2021 ◽  
Vol 22 (23) ◽  
pp. 12811
Author(s):  
Fucheng Luo ◽  
Zhen Zhang ◽  
Yu Luo

Promoting oligodendrocyte viability has been proposed as a therapeutic strategy for alleviating many neuronal diseases, such as multiple sclerosis and stroke. However, molecular pathways critical for oligodendrocyte survival under various stresses are still not well known. p53 is a strong tumor suppressor and regulates cell cycle, DNA repair and cell death. Our previous studies have shown that p53 plays an important role in promoting neuronal survival after insults, but its specific role in oligodendrocyte survival is not known. Here, we constructed the mice with oligodendrocyte-specific p53 loss by crossing TRP53flox/flox mice and CNP-cre mice, and found that p53 was dispensable for oligodendrocyte differentiation and myelin formation under physiological condition. In the experimental autoimmune encephalomyelitis (EAE) model, p53 loss of function, specifically in oligodendrocytes, did not affect the EAE disease severity and had no effect on demyelination in the spinal cord of the mice. Interestingly, p53 deficiency in oligodendrocytes significantly attenuated the demyelination of corpus callosum and alleviated the functional impairment of motor coordination and spatial memory in the cuprizone demyelination model. Moreover, the oligodendrocyte-specific loss of p53 provided protection against subcortical white matter damage and mitigated recognition memory impairment in mice in the white matter stroke model. These results suggest that p53 plays different roles in the brain and spinal cord or in response to various stresses. Thus, p53 may be a therapeutic target for oligodendrocyte prevention in specific brain injuries, such as white matter stroke and multiple sclerosis.


Diagnostics ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2161
Author(s):  
Ji Young Lee ◽  
Kyung Mi Lee ◽  
Hyug-Gi Kim ◽  
Ho-Geol Woo ◽  
Jin San Lee ◽  
...  

Purpose: The hyperintense acute reperfusion marker (HARM) is characterized by the delayed enhancement of the subarachnoid or subpial space observed on postcontrast fluid-attenuated inversion recovery (FLAIR) images, and is considered a cerebral reperfusion marker for various brain disorders, including infarction. In this study, we evaluated the cerebral distribution patterns of HARM for discriminating between an enhancing subacute infarction and an enhancing mass located in the cortex and subcortical white matter. Materials and methods: We analyzed consecutive patients who experienced a subacute ischemic stroke, were hospitalized, and underwent conventional brain magnetic resonance imaging including postcontrast FLAIR within 14 days from symptom onset, as well as those who had lesions corresponding to a clinical sign detected by diffusion-weighted imaging and postcontrast T1-weighted imaging between May 2019 and May 2021. A total of 199 patients were included in the study. Of them, 94 were finally included in the subacute infarction group. During the same period, 76 enhancing masses located in the cortex or subcortical white matter, which were subcategorized as metastasis, malignant glioma, and lymphoma, were analyzed. We analyzed the overall incidence of HARM in subacute ischemic stroke cases, and compared the enhancement patterns between cortical infarctions and cortical masses. Results: Among 94 patients with subacute stroke, 78 patients (83%) presented HARM, and among 76 patients with subcortical masses, 48 patients (63%) presented peripheral rim enhancement. Of 170 subcortical enhancing lesions, 88 (51.8%) showed HARM, and 78 (88.6%) were determined to be subacute infarction. Among 94 patients with subacute stroke, 48 patients (51%) had diffusion restrictions, and HARM was found in 39 patients (81.2%). Of the 46 patients (49%) without diffusion restriction, 39 patients (84.8%) showed HARM. Conclusions: The presence of HARM was significantly associated with subacute infarctions. For the masses, a peripheral rim enhancement pattern was observed around the mass rather than the cerebral sulci on postcontrast FLAIR.


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