Progressive Motor Deficits Research Articles

Underlying pathology identified after 20 years of disease course in two cases of slowly progressive frontotemporal dementia syndromes

ABSTRACT We report two cases from the frontotemporal lobar degeneration (FTLD) spectrum with remarkably slow progression. The first case demonstrated insidious-onset behavioral symptoms and personality changes resembling behavioral variant of frontotemporal dementia, followed a benign course over 26 years, his brain autopsy revealed the diffuse form of argyrophilic grain disease. The second case presented with slowly progressive cognitive and motor deficits, reminiscent of the corticobasal syndrome, deteriorated slowly over 22 years, his brain autopsy revealed FTLD-TDP with C9ORF72 pathology. These two cases confirm the notion of slowly progressive frontotemporal lobar degeneration caused by an underlying FTLD pathology, rather than a phenocopy.

Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal.

Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to accumulation of 15-hydroperoxy-arachidonoyl-PE (15-HpETE-PE) generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, PEBP1. As Ca2+-independent phospholipase PLA2 (iPLA2β, PLA2G6/PNPLA9 gene), can preferentially hydrolyze peroxidized phospholipids, it may eliminate ferroptotic 15-HpETE-PE death signal. Here we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2β averts ferroptosis whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6/PNPLA9 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson’s disease (PD)-associated mutation fPDR747W and found selectively decreased 15-HpETE-PE hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-CAS9-engineered PNPLA9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein mutant SNCA-A53T mice with decreased iPLA2β expression and PD-relevant phenotype. Thus, iPLA2β is a new ferroptosis regulator and its mutations may be implicated in PD pathogenesis.

Therapeutic plasma exchange as a first-choice therapy for axonal Guillain-Barré syndrome: A case-based review of the literature (Review).

Guillain-Barré syndrome is an acute immune-mediated disease that affects the peripheral nervous system, with progressive motor deficit in the limbs, sometimes involvement of the cranial nerves and possible impairment of the autonomic nervous system. Due to the respiratory and autonomic nervous dysfunction, the disease has the potential to be fatal. Although modern methods of treatment have significantly improved patient prognosis, many patients nevertheless experience significant neurological sequelae. The practical applicability of plasmapheresis was illustrated in our case report. We report the case of a 27-year-old man who had a mild viral respiratory tract infection 1 week prior to the onset of disease with gradual development of a motor deficit, urinary retention, slight swallowing difficulties and mild respiratory dysfunction. Nerve conduction studies were performed and the diagnosis of acute motor axonal neuropathy phenotypic variant of Guillain-Barré syndrome was established. Autoimmune and inflammatory diseases, infectious diseases, endocrinopathies, neoplastic diseases, intoxications, metabolic diseases and vitamin deficiencies were ruled out. Our patient attended four sessions of therapeutic plasma exchange performed using peripheral venous approach with two needles with significant recovery of the motor deficit. The patient was discharged 1 week later on maintenance kinetotherapy with further favorable evolution. In conclusion, we report a good evolution as a result of therapeutic plasma exchange in a patient with acute motor axonal neuropathy phenotypic variant of Guillain-Barré syndrome. The procedure is well-tolerated and can be performed safely by peripheral approach not only in the intensive care unit but also in a neurology clinic.

Mir21 modulates inflammation and sensorimotor deficits in cervical myelopathy: data from humans and animal models.

Degenerative cervical myelopathy is a common condition resulting from chronic compression of the spinal cord by degenerating structures of the spine. Degenerative cervical myelopathy present a wide range of outcomes, and the biological factors underlying this variability are poorly understood. Previous studies have found elevated MIR21-5p in the sub-acute and chronic neuroinflammatory environment after spinal cord injury. As chronic spinal cord neuroinflammation is a major feature of degenerative cervical myelopathy, we hypothesized that MIR21-5p may be particularly relevant to disease pathobiology, and could serve as a potential biomarker. A prospective cohort study of 69 human degenerative cervical myelopathy patients (36 male:33 female) between the ages of 30 and 78 years was performed to identify the relationship between MIR21-5p expression, symptom severity and treatment outcomes. Results from this study identified a positive correlation between elevated plasma MIR21-5p expression, initial symptom severity and poor treatment outcomes. Subsequent validation of these relationships using a mouse model of degenerative cervical myelopathy identified a similar elevation of MIR21-5p expression at 6 and 12 weeks after onset, corresponding to moderate to severe neurological deficits. To further determine how MIR21-5p affects cervical myelopathy pathobiology, this mouse model was applied to a Mir21 knockout mouse line. Deletion of the Mir21 gene preserved locomotor function on rotarod and forced swim tests, but also resulted in increased nociception based on tail flick, Von Frey filament and electrophysiological testing. Critically, Mir21 knockout mice also had reduced spinal cord inflammation, demonstrated by the reduction of Iba1+ microglia by ∼50% relative to wild-type controls. In vitro experiments using primary microglial cultures confirmed that MIR21-5p expression was greatly increased after exposure to lipopolysaccharide (pro-inflammatory), Il4 (anti-inflammatory) and hypoxia. Mir21 knockout did not appear to alter the ability of microglia to respond to these stimuli, as expression of key pro- and anti-inflammatory response genes was not significantly altered. However, target prediction algorithms identified the IL6/STAT3 pathway as a potential downstream target of MIR21-5p, and subsequent in vitro testing found that expression of components of the IL6 receptor complex, Il6ra and Il6st, were significantly higher in Mir21 knockout microglia. In aggregate, these data show that Mir21 plays a role in the progression of motor deficits and neuroinflammatory modulation in degenerative cervical myelopathy. Given this role in neuroinflammation, and its association with poor patient outcomes, MIR21-5p represents a potential therapeutic target and a new marker for prognostication.

Mood alterations in mouse models of Spinocerebellar Ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine-encoding CAG repeats in the Ataxin-1 (ATXN1) gene. SCA1 is characterized by progressive motor deficits, cognitive decline, and mood changes including anxiety and depression, with longer number of repeats correlating with worse disease outcomes. While mouse models have been very useful in understanding etiology of ataxia and cognitive decline, our understanding of mood symptoms in SCA1 has lagged. It remains unclear whether anxiety or depression stem from an underlying brain pathology or as a consequence of living with an untreatable and lethal disease. To increase our understanding of the etiology of SCA1 mood alterations, we used the elevated-plus maze, sucrose preference and forced swim tests to assess mood in four different mouse lines. We found that SCA1 knock-in mice exhibit increased anxiety that correlated with the length of CAG repeats, supporting the idea that underlying brain pathology contributes to SCA1-like anxiety. Additionally, our results support the concept that increased anxiety is caused by non-cerebellar pathology, as Purkinje cell specific SCA1 transgenic mice exhibit decreased anxiety-like behavior. Regarding the molecular mechanism, partial loss of ATXN1 may play a role in anxiety, based on our results for Atxn1 haploinsufficient and null mice.

Comparison of 5\u2009\xd7\u20095\xa0Gy and 10\u2009\xd7\u20093\xa0Gy for metastatic spinal cord compression using data from three prospective trials

BackgroundIn a palliative situation like metastatic spinal cord compression (MSCC), overall treatment time of radiotherapy should be as short as possible. This study compared 5 × 5 Gy in 1 week to 10 × 3 Gy in 2 weeks in a prospective cohort.MethodsForty patients receiving 5 × 5 Gy in a phase II trial were matched 1:2 to 213 patients receiving 10 × 3 Gy in two previous prospective studies for tumor type, ambulatory status, time developing motor deficits, interval between tumor diagnosis and MSCC and visceral metastases. These factors were consistent in all three patients (triple) used for each 1:2 matching. Groups were compared for local progression-free survival (LPFS), motor function, ambulatory status, and overall survival (OS).ResultsAfter matching, 32 triples remained for analyses (N = 96 in total). Six-month LPFS-rates were 94% after 5 × 5 Gy and 87% after 10 × 3 Gy (p = 0.36), 6-month OS-rates 43% and 35% (p = 0.74). Improvement of motor function was achieved in 59% and 34% of patients (p = 0.028); overall response rates (improvement or no further progression of motor deficits) were 94% and 89% (p = 0.71). Post-treatment ambulatory rates were 81% after 5 × 5 Gy and 85% after 10 × 3 Gy (p = 0.61). Of non-ambulatory patients, 50% (6/12) and 46% (11/24) regained the ability to walk (p = 1.00).Conclusions5 × 5 Gy in 1 week appeared similarly effective as 10 × 3 Gy in 2 weeks. These results may not be applicable to long-term survivors and should be confirmed in a randomized trial directly comparing 5 × 5 Gy and 10 × 3 Gy.Trial registration clinicaltrials.gov NCT03070431. Registered 27 February 2017.

Essential role for autophagy protein VMP1 in maintaining neuronal homeostasis and preventing axonal degeneration

Vacuole membrane protein 1 (VMP1), the endoplasmic reticulum (ER)-localized autophagy protein, plays a key role during the autophagy process in mammalian cells. To study the impact of VMP1-deficiency on midbrain dopaminergic (mDAergic) neurons, we selectively deleted VMP1 in the mDAergic neurons of VMP1fl/fl/DATCreERT2 bigenic mice using a tamoxifen-inducible CreERT2/loxp gene targeting system. The VMP1fl/fl/DATCreERT2 mice developed progressive motor deficits, concomitant with a profound loss of mDAergic neurons in the substantia nigra pars compacta (SNc) and a high presynaptic accumulation of α-synuclein (α-syn) in the enlarged terminals. Mechanistic studies showed that VMP1 deficiency in the mDAergic neurons led to the increased number of microtubule-associated protein 1 light chain 3-labeled (LC3) puncta and the accumulation of sequestosome 1/p62 aggregates in the SNc neurons, suggesting the impairment of autophagic flux in these neurons. Furthermore, VMP1 deficiency resulted in multiple cellular abnormalities, including large vacuolar-like structures (LVSs), damaged mitochondria, swollen ER, and the accumulation of ubiquitin+ aggregates. Together, our studies reveal a previously unknown role of VMP1 in modulating neuronal survival and maintaining axonal homeostasis, which suggests that VMP1 deficiency might contribute to mDAergic neurodegeneration via the autophagy pathway.

Cerebellar developmental deficits underlie neurodegenerative disorder spinocerebellar ataxia type 23.

Spinocerebellar ataxia type 23 (SCA23) is a late‐onset neurodegenerative disorder characterized by slowly progressive gait and limb ataxia, for which there is no therapy available. It is caused by pathogenic variants in PDYN, which encodes prodynorphin (PDYN). PDYN is processed into the opioid peptides α‐neoendorphin and dynorphins (Dyn) A and B; inhibitory neurotransmitters that function in pain signaling, stress‐induced responses and addiction. Variants causing SCA23 mostly affect Dyn A, leading to loss of secondary structure and increased peptide stability. PDYN R212W mice express human PDYN containing the SCA23 variant p.R212W. These mice show progressive motor deficits from 3 months of age, climbing fiber (CF) deficits from 3 months of age, and Purkinje cell (PC) loss from 12 months of age. A mouse model for SCA1 showed similar CF deficits, and a recent study found additional developmental abnormalities, namely increased GABAergic interneuron connectivity and non‐cell autonomous disruption of PC function. As SCA23 mice show a similar pathology to SCA1 mice in adulthood, we hypothesized that SCA23 may also follow SCA1 pathology during development. Examining PDYN R212W cerebella during development, we uncovered developmental deficits from 2 weeks of age, namely a reduced number of GABAergic synapses on PC soma, possibly leading to the observed delay in early phase CF elimination between 2 and 3 weeks of age. Furthermore, CFs did not reach terminal height, leaving proximal PC dendrites open to be occupied by parallel fibers (PFs). The observed increase in vGlut1 protein—a marker for PF‐PC synapses—indicates that PFs indeed take over CF territory and have increased connectivity with PCs. Additionally, we detected altered expression of several critical Ca2+ channel subunits, potentially contributing to altered Ca2+ transients in PDYN R212W cerebella. These findings indicate that developmental abnormalities contribute to the SCA23 pathology and uncover a developmental role for PDYN in the cerebellum.

Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria

Metabolic dysfunction occurs in many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood. We recently discovered a potential causal link between the branched-chain amino acid transferase BCAT-1 and the neurodegenerative movement disorder Parkinson's disease (PD). RNAi-mediated knockdown of Caenorhabditis elegans bcat-1 is known to recapitulate PD-like features, including progressive motor deficits and neurodegeneration with age, yet the underlying mechanisms have remained unknown. Using transcriptomic, metabolomic, and imaging approaches, we show here that bcat-1 knockdown increases mitochondrial respiration and induces oxidative damage in neurons through mammalian target of rapamycin-independent mechanisms. Increased mitochondrial respiration, or "mitochondrial hyperactivity," is required for bcat-1(RNAi) neurotoxicity. Moreover, we show that post-disease-onset administration of the type 2 diabetes medication metformin reduces mitochondrial respiration to control levels and significantly improves both motor function and neuronal viability. Taken together, our findings suggest that mitochondrial hyperactivity may be an early event in the pathogenesis of PD, and that strategies aimed at reducing mitochondrial respiration may constitute a surprising new avenue for PD treatment.

Recent glycemic control can predict the progressive motor deficits of acute subcortical infarction with diabetes or prediabetes.

The predictors of progressive motor deficits in acute subcortical infarctions are still controversial. It is not known whether glycemic control influences on stroke progression. A total of 268 consecutive patients with diabetes or prediabetes who had acute (< 24h) subcortical infarction were enrolled. (1) All patients were divided into 4 groups by quartile of glycated hemoglobin (HbA1c). (2) Only the patients with diabetes were divided by effective glycemic control. Progressive motor deficits were prospectively captured and defined as an increase of motor score ≥ 1 on the upper or lower limb items of the National Institute of Health Stroke Scale within 72h from stroke onset. Progressive motor deficits occur in 8/78 (10.3%) for ≤ 5.9, 15/61 (24.6%) for 6.0-6.4, 16/62 (25.8%) for 6.5-7.4, and 30/67 (44.8%) for ≥ 7.5. In diabetic patients alone, those occur in 5/37 (13.5%) for ≤ 6.5, 10/42 (23.8%) for 6.6-7.0, 12/42 (28.6%) for 7.1-8.0, and 24/50 (48.0%) for ≥ 8.1. An adjusted OR of progressive motor deficits was 2.61 (95% confidence interval [CI] 0.98-7.00, P = .056) for 6.0-6.4, 3.42 (95% CI 1.27-9.18, P = .015) for 6.5-7.4, and 6.65 (95% CI 2.38-18.62, P < .001) for ≥ 7.5. In diabetic patients alone, those were 3.15 (95% CI 0.89-11.15, P = .075) for 6.6-7.0, 2.90 (95% CI 0.79-10.61, P = .107) for 7.1-8.0, and 4.17 (95% CI 1.07-16.25, P = .038) for ≥ 8.1. The optimal cutoff value of HbA1c was 6.65% in discriminating progressive motor deficits. Increased HbA1c was associated with higher incidence of progressive motor deficits in acute subcortical infarction with diabetes and prediabetes.

Primary intradural extramedullary Ewing sarcoma: A case report and literature review.

Tumors of the spinal cord and cauda equina show a wide spectrum of histology and require careful diagnosis and treatment. Primary intradural extramedullary Ewing sarcoma (IEES) is extremely rare, and initial imaging and clinical findings for this tumor mimic those of benign intradural spinal tumors. The present report describes a case of a 35-year-old woman who presented with IEES with meningeal seeding, and the literature on the management and clinical course of these tumors was reviewed. An examination revealed right-side leg dominant rapidly progressive hypoesthesia and motor deficits. MRI identified intradural tumors at the T12-L1 and L4-5 levels. Growth and an increase in the number of intradural tumors occurred over 3 weeks. Gadolinium-contrast T1-weighted MRI revealed diffusely enhanced signals for tumorous lesions with meningeal seeding in the cervical and thoracic spinal cord. Excision of a tumor at T12-L1 was performed to alleviate the symptoms and to make a histologic diagnosis. Microscopically, the tumor consisted of dense sheets of small round cells. Immunohistochemically, tumor cells showed intense and diffuse positive staining for CD99, ETS transcription factor ERG and Fli-1 proto-oncogene, ETS transcription factor (FLI1). The sequence analysis revealed the EWS RNA binding protein 1-FLI1 fusion transcript. The lesion was diagnosed as primary intradural ES. Adjuvant chemotherapy following radiotherapy for the whole spine was performed; however, multiple brain metastases were found at 10 months after diagnosis and the patient died of diffusely disseminated disease limited to the central nervous system without evidence of distant metastases at 16 months after the initial diagnosis. In a literature review of IEES cases, the 1- and 5-year overall survival rates were 79.8 and 26.6%, respectively, and the 1-, 2- and 5-year progression-free survival rates were 61.0, 52.3 and 10.9%, respectively. Therefore, primary IEES has a poor prognosis compared with ES of bone, and novel agents and treatment strategies are required.

Poly (ADP-ribose) polymerase 1 inhibition prevents neurodegeneration and promotes α-synuclein degradation via transcription factor EB-dependent autophagy in mutant α-synucleinA53T model of Parkinson's disease.

Poly (ADP‐ribose) polymerase 1 (PARP1) is a master regulator of diverse biological processes such as DNA repair, oxidative stress, and apoptosis. PARP1 can be activated by aggregated α‐synuclein, and this process in turn exacerbates toxicity of α‐synuclein. This circle is closely linked to the evolution of Parkinson's disease (PD) that characterized by progressive neurodegeneration and motor deficits. Here, we reported the PARP1, as a novel upstream molecular of transcription factor EB (TFEB), participates in regulation of autophagy in α‐synuclein aggregated cells and mice. PARP1 inhibition not only enhances the nuclear transcription of TFEB via SIRT1 mediated down‐regulation of mTOR signaling but also reduces nuclear export of TFEB by attenuating the TFEB‐CRM1 interaction. Our results revealed that PARP1 inhibition lessened the accumulation of α‐synuclein in PD models. Also, oral administration of PARP1 inhibitor Veliparib prevented neurodegeneration and improved motor ability in α‐synucleinA53T transgenic mice. These findings identify that PARP1 signaling pathway regulates TFEB‐mediated autophagy, pointing to potential therapeutic strategy of PD via enhancing protein degradation systems.

Neurosurgical management of conus lipoma in Canada: a multi-center survey.

Lipomyelomeningocele (LMM) is a congenital spinal cord anomaly. While patients with LMM may initially be asymptomatic, neurological sequelae secondary to LMM may become apparent as the patient ages. Consequently, some pediatric neurosurgeons have advocated for upfront neurosurgical interventions irrespective of the presence of symptoms at diagnosis. By contrast, others pursue a conservative approach when overt neurological symptoms are not yet evident. In light of the various practice styles to the heterogeneous anatomical locations, symptoms, and ages associated with LMM, we have conducted a multi-center survey of Canadian pediatric neurosurgeons using clinical vignettes representative of LMM patients. An online survey of the opinions of Canadian pediatric neurosurgeons was conducted using 5 separate cases with magnetic resonance imaging (MRI) scans of the lumbar spine. Each case was accompanied with the same three clinical vignettes, which varied in severity at time of presentation: asymptomatic, progressive somatic motor deficit, or longstanding overflow incontinence. Participants were asked the question, "Would you offer surgical management?" after each clinical vignette. After the five cases and their corresponding 3 clinical vignettes, participants were asked, "If you answered yes to any of the preceding questions, what type of surgery would you perform?". Options for surgical goals and techniques included complete removal, near-total removal, debulking, detethering, and expansile duroplasty. Surgical adjuncts included CUSA, LASER, and neurophysiologic monitoring. Twenty-three responses were received from the 38 questionnaires sent out to all staff pediatric neurosurgeons across academic medical centers in Canada. This represented a response rate of 61%. Canadian pediatric neurosurgeons generally maintain a conservative approach to the surgical management of LMM as only 13% (n= 3) of surgeons indicated that they would operate in all scenarios. By contrast, 43% (n= 10) indicated surgical management in only those cases presenting with symptoms, and another 43% (n = 10) displayed a variable surgical approach. Nine percent (n= 2) of participants would not perform surgery for incontinence. The greatest level of disagreement among participants pertained to the management of asymptomatic sacral LMM where 43% of participants favored prophylactic surgery, while 57% of participants preferred conservative management. The current study highlights the differences in management of LMM among Canadian pediatric neurosurgeons and provides further support for future prospective cohort studies to develop appropriate expert opinions and guidelines such that the care of LMM patients may be according to evidence-based best practice. This is especially true for the treatment of asymptomatic patients, a patient group that would benefit from a randomized controlled trial to assess the long-term outcomes of conservative and surgical management.

Neurodegeneration and Motor Deficits in the Absence of Astrogliosis upon Transgenic Mutant TDP-43 Expression in Mature Mice

Amyotrophic lateral sclerosis is a rapidly progressing and fatal disease characterized by muscular atrophy due to loss of upper and lower motor neurons. Pathogenic mutations in the TARDBP gene encoding TAR DNA binding protein-43 (TDP-43) have been identified in familial amyotrophic lateral sclerosis. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43A315T mice) using a tetracycline-controlled inducible promotor system. Constitutive expression of transgenic TDP-43A315T in the absence of doxycycline resulted in pronounced early-onset and progressive neurodegeneration, and motor and memory deficits. Here, delayed transgene expression of TDP-43A315T by oral doxycycline treatment of iTDP-43A315T mice from birth till weaning was analyzed. After doxycycline withdrawal, transgenic TDP-43A315T expression gradually increased and resulted in cytoplasmic TDP-43, widespread ubiquitination, and cortical and hippocampal atrophy. In addition, these mice developed motor and gait deficits with underlying muscle atrophy, similar to that observed in the constitutive iTDP-43A315T mice. Surprisingly, in contrast to the constitutive iTDP-43A315T mice, these mice did not develop astrogliosis. In summary, delayed activation coupled with gradual increase in TDP-43A315T expression in the central nervous system of mature mice resulted in progressive functional deficits with neuron and muscle loss, but in the absence of a glial response. This suggests that astrocytosis does not contribute to functional deficits and neuronal loss upon TDP-43A315T expression in mature mice.

Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse model of Huntington\u2019s disease pathology

BackgroundHuntington’s disease (HD) is a dominantly inherited neurodegenerative disorder that affects cognitive and motor abilities by primarily targeting the striatum and cerebral cortex. HD is caused by a mutation elongating the CAG repeats within the Huntingtin gene, resulting in HTT protein misfolding. Although the genetic cause of HD has been established, the specific susceptibility of neurons within various brain structures has remained elusive. Microglia, which are the brain’s resident macrophages, have emerged as important players in neurodegeneration. Nevertheless, few studies have examined their implication in HD.MethodsTo provide novel insights, we investigated the maturation and dysfunction of striatal microglia using the R6/2 mouse model of HD. This transgenic model, which presents with 120+/-5 CAG repeats, displays progressive motor deficits beginning at 6 weeks of age, with full incapacitation by 13 weeks. We studied microglial morphology, phagocytic capacity, and synaptic contacts in the striatum of R6/2 versus wild-type (WT) littermates at 3, 10, and 13 weeks of age, using a combination of light and transmission electron microscopy. We also reconstructed dendrites and determined synaptic density within the striatum of R6/2 and WT littermates, at nanoscale resolution using focused ion beam scanning electron microscopy.ResultsAt 3 weeks of age, prior to any known motor deficits, microglia in R6/2 animals displayed a more mature morphological phenotype than WT animals. Microglia from R6/2 mice across all ages also demonstrated increased phagocytosis, as revealed by light microscopy and transmission electron microscopy. Furthermore, microglial processes from 10-week-old R6/2 mice made fewer contacts with synaptic structures than microglial processes in 3-week-old R6/2 mice and age-matched WT littermates. Synaptic density was not affected by genotype at 3 weeks of age but increased with maturation in WT mice. The location of synapses was lastly modified in R6/2 mice compared with WT controls, from targeting dendritic spines to dendritic trunks at both 3 and 10 weeks of age.ConclusionsThese findings suggest that microglia may play an intimate role in synaptic alteration and loss during HD pathogenesis.

4H leukodystrophy

Hypomyelinating leukodystrophy with hypodontia and hypogonadotropic hypogonadism (4H leukodystrophy), also known as POLR3-related leukodystrophy, is a genetic disorder caused by autosomal recessive mutations in the POLR3A , POLR3B , POLR1C , or POLR3K genes.1–3 Most patients have progressive motor deficits.4 We present 2 siblings with a milder phenotype and lack of disease progression previously reported within a larger cohort of patients.5

Caudal Lumbar Disc Herniations Are More Likely to Require Surgery for Symptom Resolution.

Study Design:Retrospective study.Objectives:We examined the impact that location of a lumbar disc herniation has on the likelihood that a patient will require surgery after at least 6 weeks of nonoperative management.Methods:Using ICD-10 codes M51.26 and M51.27, we identified patients at a single academic institution from 2015 to 2016 who received a diagnosis of primary lumbar radicular pain, had magnetic resonance imaging confirming a lumbar disc herniation, and underwent at least 6 weeks of nonoperative management. Patients experiencing symptoms suggesting cauda equina syndrome or progressive motor deficits were excluded.Results:Five hundred patients met inclusion/exclusion criteria. Twenty-nine (5.8%) had L3-L4 herniations, 245 (49.0%) had L4-L5 herniations, and 226 (45.2%) had L5-S1 herniations. Overall, 451 (90.2%) patients did not undergo surgery within 1 year of diagnosis. Nonsurgical patients had an average herniation size occupying 31.2% of the canal, compared with 31.5% in patients who underwent surgery. While herniation size, age, sex, and race failed to demonstrate a statistical association with the likelihood for surgery, location of disc herniation demonstrated a strong association. L3-L4 and L4-L5 herniations had odds ratios of 0.19 and 0.45, respectively, relative to L5-S1 herniations (P = .0047). Patients were more than twice as likely to require a surgery on an L5-S1 herniation in comparison with an L4-L5 herniation (P < .05). L3-L4 herniations rarely required surgery.Conclusions:Patients with caudal lumbar disc herniations were more likely to require surgery after at least 6 weeks of conservative management than those with disc herniations in the mid-lumbar spine.

Generation of a Novel Mouse Model of Parkinson’s Disease via Targeted Knockdown of Glutamate Transporter GLT-1 in the Substantia Nigra

Parkinson's disease (PD) is a common neurodegenerative disease that is characterized by pathological dopaminergic (DA) neuronal death and α-synuclein aggregation. Glutamate excitotoxicity is a well-established pathogenesis of PD that involves dysfunctional expression of glutamate transporters. Glutamate transporter-1 (GLT-1) is mainly responsible for clearance of glutamate at synapses, including DA synapses. However, the role of GLT-1 in the aberrant synaptic transmission in PD remains elusive. In the present study, we generated small-interfering RNAs (siRNAs) to knockdown GLT-1 expression in primary astrocytes, and we report that siRNA knockdown of astrocytic GLT-1 decreased postsynaptic density-95 (PSD-95) expression in neuron-astrocyte cocultures in vitro. Using adeno-associated viruses (AAVs) targeting GLT-1 short-hairpin RNA (shRNA) sequences with a glial fibrillary acidic protein (GFAP) promoter, we abolished astrocytic GLT-1 expression in the substantia nigra pars compacta (SNpc) of mice. We found that GLT-1 deficiency in the SNpc induced parkinsonian phenotypes in terms of progressive motor deficits and nigral DA neuronal death in mice. We also found that there were reactive astrocytes and microglia in the SNpc upon GLT-1 knockdown. Furthermore, we used RNA sequencing to determine altered gene expression patterns upon GLT-1 knockdown in the SNpc, which revealed that disrupted calcium signaling pathways may be responsible for GLT-1 deficiency-mediated DA neuronal death in the SNpc. Taken together, our findings provide evidence for a novel role of GLT-1 in parkinsonian phenotypes in mice, which may contribute to further elucidation of the mechanisms of PD pathogenesis.

Inhibition of ER stress improves progressive motor deficits in a REEP1-null mouse model of hereditary spastic paraplegia.

ABSTRACTHereditary spastic paraplegias (HSPs) are genetic neurodegenerative diseases. HSPs are characterized by lower-extremity weakness and spasticity. However, there is no specific clinical treatment strategy to prevent or reverse nerve degeneration in HSPs. Mutations in receptor expression-enhancing protein 1 (REEP1) are well-recognized and relatively common causes of autosomal dominant HSPs. REEP1 modifies the endoplasmic reticulum (ER) shape, and is implicated in the ER stress response. Defects in the ER stress response seem to be crucial mechanisms underlying HSP neurodegeneration. Here, we report that REEP1−/− mice exhibit progressive motor deficits, along with denervation of neuromuscular junctions and increased ER stress. Moreover, marked axonal degeneration and morphological abnormalities are observed. In this study, we treated both REEP1−/− and wild-type (WT) mice with salubrinal, which is a specific inhibitor of ER stress, and we observed increased nerve-muscle connections and enhanced motor functions. Our data highlight the importance of ER homeostasis in HSPs, providing new opportunities for HSP treatment.

Long Term Radiological and Clinical Outcome of Symptomatic Lumbar Intraspinal Synovial Cyst: A Retrospective 4-Year Study.

To examine the prevalence of symptomatic lumbar synovial facet cysts in lumbar spinal magnetic resonance imaging (MRI) of patients who admitted to neurosurgery clinic, retrospectively. Also, we aimed to report the clinic and radiologic outcome of patients with symptomatic spinal synovial cyst, who undergo conservative treatment. One thousand two hundred forty-three patients who admitted to Ordu University Neurosurgery outpatient clinic between 2015-2019 and underwent lumbosacral MRI and lumbosacral computed tomography examinations were reviewed retrospectively. The disappearance of cysts during radiologic follow up was accepted as spontaneous complete resolution, besides reduction in cyst dimensions and/or contrast enhancement were considered as radiologic regression. Decrease in radiculopathy, back pain and neurologic deficit complaints were also considered as clinical improvement. Thirteen patients (8 men, 5 women) with lumbar synovial cysts who admitted to the neurosurgery outpatient clinic with low back and radicular pain complaints were included in the study. Nine patients (69.2%) had clinical and radiological improvement, 1 female patient (7.7%) was operated due to the leg pain, progressive motor deficit and lumbar disc hernia. Radiological spontaneous complete resolution was detected in 3 patients (23.1%). Spontaneous complete resolution period was determined between 3 months to 24 months. The symptomatic lumbosacral synovial cyst treatment algorithm has not been fully demonstrated. However, as in our series, spontaneous complete resolution of cysts and effectiveness of conservative treatment in symptomatic patients should not to be underestimated and immediate invasive procedures should be postponed.