Including Motor Deficits Research Articles

Clinical pattern, neuroimaging findings and outcome of Acute Disseminated Encephalomyelitis in children: A retrospective study.

To determine the clinical spectrum, neuroimaging findings, and outcome of Acute Disseminated Encephalomyelitis (ADEM) in children. We conducted a descriptive cross sectional study of all children aged 6 months to 18 years, diagnosed with ADEM at Aga Khan University Hospital, Karachi from January 2018 till December 2022. This retrospective study enrolled 30 cases of ADEM, with a mean age of 6.43 ± 4.079, including 13 males and 17 females. The average hospital stay was 7.29 ± 4.379 days. The most common clinical features were fever, headache, and altered consciousness, while motor deficit was observed in 15 (53.5%) patients. Abnormal cerebrospinal fluid was found in 14 (46.6%) patients. Brain MRI identified bilateral and multifocal lesions in 22 (78.6%) patients, with brainstem lesions detected in 7 (25%) patients. Treatment included IV methylprednisolone (22; 73%), IVIG (9; 30%), or both (6; 20%). Clinical improvement was observed in 25 (89.3%) patients, with residual weakness present in eight (26%) patients at discharge. There was one reported death. Long-term complications included motor deficits, seizures, poor scholastic performance, and behavioral issues. The clinical presentation of ADEM is variable, but the most common symptoms are fever, headache, and altered consciousness. Despite generally favorable outcome, long-term monitoring revealed that patients may experience motor deficits, seizures, cognitive impairment, and academic difficulties.

A Comprehensive Examination of Clinical Characteristics and Determinants of Long-Term Outcomes in Pediatric Cerebral Sinus Venous Thrombosis

BackgroundTo analyze the clinical and neuroimaging features, risk factors, treatment choices, and long-term clinical outcomes in children with cerebral sinus venous thrombosis (CSVT). MethodsThis is a retrospective cohort study of children diagnosed with CSVT between 2002 and 2018 at Texas Children's Hospital. ResultsA total of 183 children (male: 62.3%) with CSVT were included. The average presenting age was 7.7 years (S.D.: 5.6). The mean follow-up duration was 33.7 months (S.D.: 38.6). The most common presenting clinical feature was headache (36.6%). Head and neck infections other than meningitis (36.6%) were the most common risk factors. Prevalent neurological examination findings included motor deficit (21.3%) and altered mental status (AMS, 20.2%). Neuroimaging features included hemorrhagic infarction (19.6%), ischemic infarction (8.2%), and intracranial hemorrhage without infarction (5.5%). The most common site of thrombosis was the superior sagittal sinus (37.2%), with 78.2% of patients demonstrating involvement of multiple sinuses. Treatment of choice was low-molecular-weight heparin in 69.4% of patients. Factors associated with worse clinical outcomes included head and neck infections, malignancy (other than hematologic), cardiac disease, and recent surgery; seizure and dehydration on initial presentation; motor abnormalities and AMS on initial examination; ischemic infarct only; and involvement of vein of Trolard on neuroimaging. Thrombus condition on repeat imaging, receiving any anticoagulant/antithrombotic treatment, treatment duration, or follow-up duration was not associated with severity of long-term outcome. ConclusionsCSVT may lead to unfavorable long-term outcomes in a remarkable portion of pediatric patients. Thus, a high index of suspicion and early and appropriate management of pediatric CSVT is imperative.

Development of a fluorescence and quencher-based FRET assay for detection of endogenous peptide:N-glycanase/NGLY1 activity

Cytosolic peptide:N-glycanase (PNGase/NGLY1 in mammals) catalyzes deglycosylation of N-glycans on glycoproteins. A genetic disorder caused by mutations in the NGLY1 gene leads to NGLY1 deficiency, with symptoms including motor deficits and neurological problems. Effective therapies have not been established, though a recent study used the administration of an adeno-associated viral vector expressing human NGLY1 to dramatically rescue motor functions in young Ngly1–/– rats. Thus, early therapeutic intervention may improve symptoms arising from central nervous system dysfunction, and assay methods for measuring NGLY1 activity in biological samples are critical for early diagnostics. In this study, we established an assay system for plate-based detection of endogenous NGLY1 activity using a FRET-based probe. Using this method, we revealed significant changes in NGLY1 activity in rat brains during aging. This novel assay offers reliable disease diagnostics and provides valuable insights into the regulation of PNGase/NGLY1 activity in diverse organisms under different stress conditions.

Reversible Cerebral Vasoconstriction Syndrome in Children and Adolescents: A Case Series and Literature Review

Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical radiographic phenomenon characterized by thunderclap headaches and transient vasoconstriction of cerebral vessels, which typically resolve within 3 months of symptom onset. Although RCVS has been extensively studied in adults, research on this condition in pediatric populations is limited, likely due to its perceived rarity. This comprehensive review aims to bridge the knowledge gap by examining the clinical presentation, diagnostic methods, treatment strategies, and prognostic outcomes of pediatric RCVS cases, including two case reports contributed by the authors. This study demonstrates an inconclusive sex distribution of RCVS in children, attributed to the scarcity of comprehensive studies of this demographic. Additionally, we identified several predictors of adverse neurological outcomes in children with RCVS, including motor deficits, aphasia, hypertension, and renal disease. This study offers a thorough overview of RCVS in the pediatric population, providing valuable insights to inform future research in this area.

Isolated reversible involvement of bilateral internal capsule on magnetic resonance imaging in case of acute hypoglycemic encephalopathy: A case report

Hypoglycemic encephalopathy (HE) is a metabolic disorder that can lead to morbid manifestations including motor deficits, transient memory loss, persistent vegetative state, and even deep coma. Due to potential clinical symptom overlap with acute stroke, accurate diagnosis is very crucial. Besides the patient’s medical history and routine blood investigations, magnetic resonance imaging (MRI), particularly diffusion-weighted imaging (DWI), plays a valuable role in diagnosing HE. We present a case of acute hypoglycemia with reversible changes in the bilateral internal capsule seen on DWI-MRI.

Tumefactive demyelinating lesions: a retrospective cohort study in Thailand

Tumefactive demyelinating lesions (TDL), characterized by large (≥ 2 cm) demyelinating lesions mimicking tumors, are a rare manifestation of the central nervous system inflammatory demyelinating diseases (CNS-IDD). Distinguishing TDL from other brain lesions can be challenging, often necessitating biopsy or advanced diagnostics. The natural history of TDL varies among races. This study aimed to assess demographics, clinical and radiological features, laboratory findings, management, and outcomes of Thai patients with TDL. We retrospectively reviewed records of twenty-six patients with TDL from the Multiple Sclerosis and Related Disorders registry from two tertiary medical centers. Among 1102 CNS-IDD patients, 26 (2.4%) had TDL. The median age at TDLs onset was 34.5 years (range 17–75); 69.2% were female. Over 70% manifested TDL as their initial CNS-IDD presentation. Common presenting symptoms included motor deficits, sensory disturbances, and cognitive problems. About two-fifths exhibited multiple lesions, most frequently in the frontoparietal region (46.2%). Half of the patients showed an incomplete ring on post-contrast T1-weighted imaging, with peripheral diffusion-weighted imaging restriction in twenty-one patients. T2-hypointense rims were present in thirteen (56.5%) patients. Brain biopsy was performed in 12 cases (46.1%). Serum aquaporin-4 immunoglobulin was positive in 16.7% of tested (4/24) cases. Serum myelin oligodendrocyte glycoprotein immunoglobulin was negative in all thirteen patients tested. Twenty patients (76.9%) received intravenous corticosteroids for TDL attacks. After the median follow-up period of 48 months (range 6–300), 23.1% experienced CNS-IDD relapses. Median Expanded Disability Status Scale at TDL diagnosis was 4.3 (range 0.0–9.5), and improved to 3.0 (range 0.0–10.0) at the last follow-up. This study suggested that TDL were rare among Thai CNS-IDD patients, frequently presenting as a monophasic condition with a favorable outcome.

Impaired Voluntary Activation of an Ankle Dorsiflexor Muscle Predicts Walking Capacity in Multiple Sclerosis

Background and Purpose Walking impairments are highly prevalent in people with Multiple Sclerosis (pwMS) and are related to factors including motor deficits and balance. Reductions in voluntary activation (VA) (i.e., reduced neural drive known as central fatigability) is a key contributor to motor deficits during fatiguing tasks in pwMS; however, the relationship between central fatigability and walking function is poorly understood. The purpose of this study was to determine associations between reductions in VA after a fatiguing task and walking capacity (WC) in pwMS and controls. Methods 19 pwMS (female=9) and 10 age-matched controls (female=6) participated. PwMS were sub-grouped for disease severity into those mildly affected (n=11, female=5, EDSS=2.5-4.0) and moderately affected (n=8, female=4, EDSS= 4.5-6.5). Twitch interpolation during a maximal voluntary contraction quantified VA of the tibialis anterior muscle before and immediately after a fatiguing time-to-task failure isometric task performed at 50% of maximal strength. The 6-minute walk test determined baseline WC. Values are mean ± SD. Results Moderately affected pwMS showed greater central fatigability after the fatiguing task compared with mildly affected pwMS (p=0.01), and controls (p=0.07) (moderately affected= 23.5% ± 24.9, mildly affected= 0.3% ± 5.4, controls= 6.4% ± 14.4). Both groups of pwMS showed lower WC than controls (moderately affected= 299.5m ± 75.2, mildly affected= 527.7m ± 68.9, controls= 613.7m ± 88.9, p<0.001). Further analyses revealed an association between central fatigability and WC, but only in the moderately affected pwMS (R2= 0.7, standardized estimate= -0.8, t=-3.8, p=0.009). Discussion Impaired neural drive of the ankle dorsiflexor muscles is a predictor of WC in pwMS who experience greater disease severity. Thus, mechanisms for limitation in walking function may be different based on disease severity in pwMS and this knowledge may assist in optimizing rehabilitation strategies to improve walking function in pwMS. Walking impairments are highly prevalent in people with Multiple Sclerosis (pwMS) and are related to factors including motor deficits and balance. Reductions in voluntary activation (VA) (i.e., reduced neural drive known as central fatigability) is a key contributor to motor deficits during fatiguing tasks in pwMS; however, the relationship between central fatigability and walking function is poorly understood. The purpose of this study was to determine associations between reductions in VA after a fatiguing task and walking capacity (WC) in pwMS and controls. 19 pwMS (female=9) and 10 age-matched controls (female=6) participated. PwMS were sub-grouped for disease severity into those mildly affected (n=11, female=5, EDSS=2.5-4.0) and moderately affected (n=8, female=4, EDSS= 4.5-6.5). Twitch interpolation during a maximal voluntary contraction quantified VA of the tibialis anterior muscle before and immediately after a fatiguing time-to-task failure isometric task performed at 50% of maximal strength. The 6-minute walk test determined baseline WC. Values are mean ± SD. Moderately affected pwMS showed greater central fatigability after the fatiguing task compared with mildly affected pwMS (p=0.01), and controls (p=0.07) (moderately affected= 23.5% ± 24.9, mildly affected= 0.3% ± 5.4, controls= 6.4% ± 14.4). Both groups of pwMS showed lower WC than controls (moderately affected= 299.5m ± 75.2, mildly affected= 527.7m ± 68.9, controls= 613.7m ± 88.9, p<0.001). Further analyses revealed an association between central fatigability and WC, but only in the moderately affected pwMS (R2= 0.7, standardized estimate= -0.8, t=-3.8, p=0.009). Impaired neural drive of the ankle dorsiflexor muscles is a predictor of WC in pwMS who experience greater disease severity. Thus, mechanisms for limitation in walking function may be different based on disease severity in pwMS and this knowledge may assist in optimizing rehabilitation strategies to improve walking function in pwMS.

KMT5B is required for early motor development.

Disruptive variants in lysine methyl transferase 5B (KMT5B/SUV4-20H1) have been identified as likely-pathogenic among humans with neurodevelopmental phenotypes including motor deficits (i.e., hypotonia and motor delay). However, the role that this enzyme plays in early motor development is largely unknown. Using a Kmt5b gene trap mouse model, we assessed neuromuscular strength, skeletal muscle weight (i.e., muscle mass), neuromuscular junction (NMJ) structure, and myofiber type, size, and distribution. Tests were performed over developmental time (postnatal days 17 and 44) to represent postnatal versus adult structures in slow- and fast-twitch muscle types. Prior to the onset of puberty, slow-twitch muscle weight was significantly reduced in heterozygous compared to wild-type males but not females. At the young adult stage, we identified decreased neuromuscular strength, decreased skeletal muscle weights (both slow- and fast-twitch), increased NMJ fragmentation (in slow-twitch muscle), and smaller myofibers in both sexes. We conclude that Kmt5b haploinsufficiency results in a skeletal muscle developmental deficit causing reduced muscle mass and body weight.

What Is Currently Known about Intramedullary Spinal Cord Abscess among Children? A Concise Review

Intramedullary spinal cord abscesses (ISCA) are rare. Typical symptoms include signs of infection and neurological deficits. Symptoms among (younger) children can be highly uncharacteristic. Therefore, prompt and proper diagnoses may be difficult. Typical therapeutic options include antibiotics and neurosurgical exploration and drainage. In this review, we analyze published cases of ISCA among children. Most pediatric cases were found to be under the age of 6 years. The typical symptoms included motor deficits in 89.06%, infection signs in 85.94%, and sensory deficits in 39.06%. Urinary dysfunction was observed in 43.75%, and bowel dysfunction in 17.19%. The predisposing factors included dermal sinuses, (epi)dermoid cysts, prior infection, iatrogenic disorder, and trauma. The most common pathogens were: Staphylococcus aureus, Mycobacterium tuberculosis, Escherichia coli, and Proteus mirabilis. The pediatric population has good outcomes as 45.93% of patients had complete neurological recovery and only 26.56% had residual neurological deficits. Fifteen (23.44%) had persistent neurological deficits. Only one (1.56%) patient died with an ISCA. In two (3.13%) cases, there were no details about follow-up examinations.

Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome.

Leigh syndrome is a mitochondrial disease characterized by neurodegeneration, neuroinflammation, and early death. Mice lacking NDUFS4, a mitochondrial complex I subunit (Ndufs4 KO mice), have been established as a good animal model for studying human pathology associated with Leigh syndrome. As the disease progresses, there is an increase in neurodegeneration and neuroinflammation, thereby leading to deteriorating neurological symptoms, including motor deficits, breathing alterations, and eventually, death of the animal. However, despite the magnitude of neuroinflammation associated with brain lesions, the role of neuroinflammatory pathways and their main cellular components have not been addressed directly as relevant players in the disease pathology. Here, we investigate the role of microglial cells, the main immune cells of the CNS, in Leigh‐like syndrome pathology, by pharmacologically depleting them using the colony‐stimulating factor 1 receptor antagonist PLX3397. Microglial depletion extended lifespan and delayed motor symptoms in Ndufs4 KO mice, likely by preventing neuronal loss. Next, we investigated the role of the major cytokine interleukin‐6 (IL‐6) in the disease progression. IL‐6 deficiency partially rescued breathing abnormalities and modulated gliosis but did not extend the lifespan or rescue motor decline in Ndufs4 KO mice. The present results show that microglial accumulation is pathogenic, in a process independent of IL‐6, and hints toward a contributing role of neuroinflammation in the disease of Ndufs4 KO mice and potentially in patients with Leigh syndrome.

Mortality and morbidity in surgically treated patients with petroclival meningiomas: a systematic review and meta-analysis of case series

Background Reports on petroclival meningioma (PCM) surgical mortality and morbidity often deviate from established standards; as such, a comprehensive summary is lacking. Methods Eligibility/sources. Peer-reviewed case series of at least 10 PCM patients identified from PubMed, Web of Science, Ovid, or Google Scholar. Outcomes. Primary: mortality, tumor recurrence, any cranial nerve deficit (CND); other: individual CNDs, other complications. Data synthesis. Random-effects meta-analysis/meta-regression [effects: surgical approach (supratentorial, S; infratentorial, I; combined, (C), average age and follow-up, sample size, and percent of patients with gross-total resection (GTR)] of logit-transformed proportions. Results Data. 73 case-series/3553 patients. Mortality. Adjusted predicted mortalities of 2.4%, 2.5%, and 1.2% (50-month follow-up) for the S, I, and C approaches, respectively, with the upper limits of the 95% credibility intervals at 3.3%, 3.7%, and 3.6%, respectively. Recurrence. Adjusted predicted recurrences of 5.5%, 11.1%, and 12.0% (50-month follow-up and 57% GTR) for the S, I, and C approaches, respectively; recurrence was positively associated with follow-up period and negatively associated with having received GTR. At all covariates at median values but at GTR 90% predictions: 3.1% (95%CI 3.1–9.8), 6.3% (3.8–10.4), and 6.9% (3.4–13.2) with the S, I, and C; prediction credibility intervals 1–4% and 22.4%. Any CND. Adjusted predicted probabilities of 37.2%, 23.4%, and 29.5% (at median covariate values) for the S, I, and C approaches, respectively; prediction credibility intervals ranged from <10% to 78%. Other outcomes. The most common individual CNDs were nVII (14.4%), nV (11.5%), and nIII (10.2%); other common complications included motor deficit (10.8%), infection (9.8%), and CSF leak (7.5%). Conclusion This is the first systematic review on PCM surgical mortality, recurrence, and morbidity. Outcomes differ between surgical approaches and reporting quality varies greatly.

Preclinical Evaluation of Polymeric Nanocomposite Containing Pregabalin for Sustained Release as Potential Therapy for Neuropathic Pain.

This study offers a novel oral pregabalin (PG)-loaded drug delivery system based on chitosan and hypromellose phthalate-based polymeric nanocomposite in order to treat neuropathic pain (PG-PN). PG-PN has a particle size of 432 ± 20 nm, a polydispersity index of 0.238 ± 0.001, a zeta potential of +19.0 ± 0.9 mV, a pH of 5.7 ± 0.06, and a spherical shape. Thermal and infrared spectroscopy confirmed nanocomposite generation. PG-PN pharmacokinetics was studied after a single oral dose in male Wistar rats. PG-PN showed greater distribution and clearance than free PG. The antinociceptive effect of PG-PN in neuropathic pain rats was tested by using the chronic constriction injury model. The parameter investigated was the mechanical nociceptive threshold measured by the von Frey filaments test; PG-PN showed a longer antinociceptive effect than free PG. The rota-rod and barbiturate sleep induction procedures were used to determine adverse effects; the criteria included motor deficit and sedative effects. PG-PN and free PG had plenty of motors. PG-PN exhibited a less sedative effect than free PG. By prolonging the antinociceptive effect and decreasing the unfavorable effects, polymeric nanocomposites with pregabalin have shown promise in treating neuropathic pain.

Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia.

Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination with chloroquine, a lysosomal inhibitor that enhanced DAT expression in a heterologous expression system. Together, these studies shed some light on how a DTDS-linked DAT mutation underlies DA dysfunction and, possibly, clinical phenotypes shared by DTDS and PD.

Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration in Drosophila.

Alpha-synuclein (α-syn) mislocalization and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinson’s disease, Parkinson’s disease with dementia and dementia with Lewy bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying α-syn accumulation and toxicity in a Drosophila model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human α-syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, cysteine string protein, synapsin, and syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These α-syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing Drosophila that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of dementia with Lewy bodies. Together, these findings demonstrate that presynaptic accumulation of α-syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that α-syn-mediated synaptopathy is an initiating cause of age-related neurodegeneration.

What, When and How to Measure-Peripheral Biomarkers in Therapy of Huntington's Disease.

Among the main challenges in further advancing therapeutic strategies for Huntington’s disease (HD) is the development of biomarkers which must be applied to assess the efficiency of the treatment. HD is a dreadful neurodegenerative disorder which has its source of pathogenesis in the central nervous system (CNS) but is reflected by symptoms in the periphery. Visible symptoms include motor deficits and slight changes in peripheral tissues, which can be used as hallmarks for prognosis of the course of HD, e.g., the onset of the disease symptoms. Knowing how the pathology develops in the context of whole organisms is crucial for the development of therapy which would be the most beneficial for patients, as well as for proposing appropriate biomarkers to monitor disease progression and/or efficiency of treatment. We focus here on molecular peripheral biomarkers which could be used as a measurable outcome of potential therapy. We present and discuss a list of wet biomarkers which have been proposed in recent years to measure pre- and postsymptomatic HD. Interestingly, investigation of peripheral biomarkers in HD can unravel new aspects of the disease pathogenesis. This especially refers to inflammatory proteins or specific immune cells which attract scientific attention in neurodegenerative disorders.

TMS Correlates of Pyramidal Tract Signs and Clinical Motor Status in Patients with Cervical Spondylotic Myelopathy.

Background: While the association between motor-evoked potential (MEP) abnormalities and motor deficit is well established, few studies have reported the correlation between MEPs and signs of pyramidal tract dysfunction without motor weakness. We assessed MEPs in patients with pyramidal signs, including motor deficits, compared to patients with pyramidal signs but without weakness. Methods: Forty-three patients with cervical spondylotic myelopathy (CSM) were dichotomized into 21 with pyramidal signs including motor deficit (Group 1) and 22 with pyramidal signs and normal strength (Group 2), and both groups were compared to 33 healthy controls (Group 0). MEPs were bilaterally recorded from the first dorsal interosseous and tibialis anterior muscle. The central motor conduction time (CMCT) was estimated as the difference between MEP latency and peripheral latency by magnetic stimulation. Peak-to-peak MEP amplitude and right-to-left differences were also measured. Results: Participants were age-, sex-, and height-matched. MEP latency in four limbs and CMCT in the lower limbs were prolonged, and MEP amplitude in the lower limbs decreased in Group 1 compared to the others. Unlike motor deficit, pyramidal signs were not associated with MEP measures, even when considering age, sex, and height as confounding factors. Conclusions: In CSM, isolated pyramidal signs may not be associated, at this stage, with MEP changes.

A Mouse Model of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)-Induced Parkinson Disease Shows that 2-Aminoquinoline Targets JNK Phosphorylation.

BackgroundThe pathological features of Parkinson disease (PD) include motor deficits, glial cell activation, and neuroinflammation. The neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has an oxidation product, 1-methyl-4-phenylpyridinium ion (MPP+). This study aimed to investigate the effects of 2-aminoquinoline on motor deficits in a mouse model of MPTP-induced PD and cultured mouse astrocytes treated with MPP+, to determine the effects on astrocyte proliferation and apoptosis.Material/MethodsMotor deficits in the mouse model of MPTP-induced PD were investigated using the climbing time, suspension time, and swim time tests. Cultured mouse astrocytes were treated with MPP+, and mice with MPTP-induced PD were treated with increasing doses of 2-aminoquinoline. The MTT assay was used to measure astrocyte viability. Astrocyte apoptosis was assessed by confocal fluorescence microscopy using Annexin-V and fluorescein isothiocyanate (FITC) staining. Western blot measured the levels of Bax, p-JNK, Bcl-2, and caspase-3.ResultsIn the mouse model of MPTP-induced PD, motor deficit tests showed that 2-aminoquinoline reduced the impaired motor function during the climbing time, the suspension time, and the swim time tests in a dose-dependent manner. Pre-treatment with 2-aminoquinoline significantly reduced the proliferation and apoptosis of astrocytes induced by MPP+ in vitro, in a dose-dependent manner (P<0.05). The levels of p-JNK and cleaved caspase-3 levels were significantly reduced in astrocytes treated with MPP+ following pre-treatment with 2-aminoquinoline, which also reversed the increase in the Bax/Bcl-2 ratio.ConclusionsIn the mouse model of MPTP-induced PD, 2-aminoquinoline reduced motor deficiencies, inhibited MPP+ activated astrocyte apoptosis, and regulated the Bax/Bcl-2 ratio by targeting p-JNK.

Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease.

Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as glucosylsphingosine substrate accumulations as a direct result of the glucocerebrosidase deficiency. Neuronal symptoms include motor deficits and strong alterations in the cerebellum. To evaluate the effect of new compounds for the treatment of this devastating disease, animal models are needed that closely mimic the human phenotype. The 4L/PS-NA mouse as model of Gaucher disease is shown to present reduced glucocerebrosidase activity similar to human cases but an in-depth characterization of the model was still not performed. We therefore analyzed 4L/PS-NA mice for visceral alterations, motor deficits and also neuronal changes like glucocerebrosidase activity, substrate levels and neuroinflammation. A special focus was set at pathological changes of the cerebellum. Our results show that 4L/PS-NA mice have strongly enlarged visceral organs that are infiltrated by enlarged leukocytes and macrophages. Furthermore, animals present strong motor deficits that are accompanied by increased glucosylceramide and glucosylsphingosine levels in the brain, astrocytosis and activated microglia in the cortex and hippocampus as well as reduced calbindin levels in the cerebellum. The latter was directly related to a strong Purkinje cell loss. Our results thus provide a detailed characterization of the 4L/PS-NA mouse model over age showing the translational value of the model and validating its usefulness for preclinical efficiency studies to evaluate new compounds against Gaucher disease.

Changes in motor behavior, neuropathology, and gut microbiota of a Batten disease mouse model following administration of acidified drinking water

CLN3 mutations cause the fatal neurodegenerative disorder, CLN3 Batten disease. The Cln3−/− mouse model displays characteristic features of the human disease including motor deficits. When mice received acidified drinking water (pH 2.5–2.9) instead of normal tap water (pH 8.4) for several generations, the motor skills of Cln3−/− mice normalized to control levels, indicating a disease-modifying effect of acidified water. Here we investigated if acidified water administered from postnatal day 21 has therapeutic benefits in Cln3−/− mice. Indeed, acidified water temporarily attenuated the motor deficits, had beneficial effects on behavioral parameters and prevented microglial activation in the brain of Cln3−/− mice. Interestingly, in control mice, acidified drinking water caused brain region-specific glial activation and significant changes in motor performance. Since the gut microbiota can influence neurological functions, we examined it in our disease model and found that the gut microbiota of Cln3−/− mice was markedly different from control mice, and acidified water differentially changed the gut microbiota composition in these mice. These results indicate that acidified water may provide therapeutic benefit to CLN3 Batten disease patients, and that the pH of drinking water is a major environmental factor that strongly influences the results of murine behavioral and pathological studies.

Outcomes of Surgery for Brainstem Cavernous Malformations: A Systematic Review.

Background and Purpose- The goal of this study was to systematically review the outcomes and complications after surgical resection of brain stem cavernous malformations (BCMs). Methods- A systematic literature review was performed using the PubMed database for studies published between 1986 and 2018. All studies comprising ≥2 patients with surgically resected BCMs and available follow-up data were included. Data extracted from studies included patient demographics, BCM location, and surgical outcomes. Results- Eighty-six studies comprising 2493 patients (adult and pediatric) were included for final analysis. Complete resection was achieved in 92.3% (fixed-effects pooled estimate [FE], 92.9% [91.7%-94.0%]; random-effects pooled estimate [RE], 89.4% [86.5%-92.0%]) of patients, and rehemorrhage of residual BCMs occurred in 58.6% (FE, 58.8% [49.7%-67.6%]; RE, 57.2% [43.5%-70.2%]). Postoperative morbidity occurred in 34.8% (FE, 30.9% [29.0%-32.8%]; RE, 31.1% [25.8%-36.6%]) of patients. Postoperative morbidities included motor deficit in 11.0% (FE, 9.9% [8.1%-11.7%]; RE, 11.1% [7.0%-16.0%]), sensory deficit in 6.7% (FE, 6.3% [4.8%-7.9%]; RE, 7.6% [4.5%-11.5%]), tracheostomy/gastrostomy in 6.0% (FE, 5.2% [4.3%-6.1%]; RE, 3.8% [2.6%-5.3%]), and other cranial nerve deficits in 29.4% (FE, 27.6% [25.3%-29.9%]; RE, 33.9% [25.7%-42.6%]) of patients. At final follow-up, 57.9% (FE, 57.6% [55.6%-59.6%]; RE, 57.2% [52.1%-62.3%]) and 25.9% (FE, 24.1% [22.4%-25.9%]; RE, 18.5% [14.6%-22.8%]) of patients had improvement and stability of preoperative symptoms, respectively. Mortality rate was 1.6% (FE, 1.9% [1.4%-2.5%]; RE, 1.8% [1.4%-2.5%]). Conclusions- High cure rates and low rates of postoperative morbidity can be achieved with surgery in patients with BCMs. Most patients had improved preoperative symptoms at final follow-up. To avoid rehemorrhage, complete resection should be the goal of surgery.