New Targets in Atherosclerosis: Vascular Smooth Muscle Cell Plasticity and Macrophage Polarity.

PURPOSE: Despite an increase in treatment options, and substantial reductions in cardiovascular mortality over the past half-century, atherosclerosis remains the most prevalent cause of premature mortality worldwide. The development of innovative new therapies is crucial to further minimize atherosclerosis-related deaths. The diverse array of cell phenotypes derived from vascular smooth muscle cells (SMCs) and macrophages within atherosclerotic plaques are increasingly becoming recognized for their beneficial and detrimental roles in plaque stability and disease burden. This review explores how contemporary transcriptomics and fate-mapping studies have revealed vascular cell plasticity as a relatively unexplored target for therapeutic intervention. METHODS: Recent literature for this narrative review was obtained by searching electronic databases (ie, Google Scholar, PubMed). Additional studies were sourced from reference lists and the authors' personal databases. FINDINGS: The lipid-rich and inflammatory plaque milieu induces SMC phenotypic switching to both beneficial and detrimental phenotypes. Likewise, macrophage heterogeneity increases with disease burden to a variety of pro-inflammatory and anti-inflammatory activation states. These vascular cell phenotypes are determinants of plaque structure stability, and it is therefore highly likely that they influence clinical outcomes. Development of clinical treatments targeting deleterious phenotypes or promoting pro-healing phenotypes remains in its infancy. However, existing treatments (statins) have shown beneficial effects toward macrophage polarization, providing a rationale for more targeted approaches. In contrast, beneficial SMC phenotypic modulation with these pharmacologic agents has yet to be achieved. The range of modulated vascular cell phenotypes provides a multitude of novel targets and the potential to reduce future adverse events. IMPLICATIONS: Vascular cell phenotypic heterogeneity must continue to be explored to lower cardiovascular events in the future. The rapidly increasing weight of evidence surrounding the role of SMC plasticity and macrophage polarity in plaque vulnerability provides a strong foundation upon which development of new therapeutics must follow. This approach may prove to be crucial in reducing cardiovascular events and improving patient benefit in the future.

Predictors of poor outcome following lumbar spinal fusion surgery: a prospective observational study to derive two clinical prediction rules using British Spine Registry data.

PURPOSE: Lumbar spinal fusion surgery (LSFS) is common for lumbar degenerative disorders. The objective was to develop clinical prediction rules to identify which patients are likely to have a favourable outcome to inform decisions regarding surgery and rehabilitation. METHODS: A prospective observational study recruited 600 (derivation) and 600 (internal validation) consecutive adult patients undergoing LSFS for degenerative lumbar disorder through the British Spine Registry. Definition of good outcome (6 weeks, 12 months) was reduction in pain intensity (Numerical Rating Scale, 0-10) and disability (Oswestry Disability Index, ODI 0-50) > 1.7 and 14.3, respectively. Linear and logistic regression models were fitted and regression coefficients, Odds ratios and 95% CIs reported. RESULTS: Lower BMI, higher ODI and higher leg pain pre-operatively were predictive of good disability outcome, higher back pain was predictive of good back pain outcome, and no previous surgery and higher leg pain were predictive of good leg pain outcome; all at 6 weeks. Working and higher leg pain were predictive of good ODI and leg pain outcomes, higher back pain was predictive of good back pain outcome, and higher leg pain was predictive of good leg pain outcome at 12 months. Model performance demonstrated reasonable to good calibration and adequate/very good discrimination. CONCLUSIONS: BMI, ODI, leg and back pain and previous surgery are important considerations pre-operatively to inform decisions for surgery. Pre-operative leg and back pain and work status are important considerations to inform decisions for management following surgery. Findings may inform clinical decision making regarding LSFS and associated rehabilitation.

Identification of Intervention Opportunities through Assessment of the Appropriateness of Antibiotic Prescribing in Surgical Patients in a UK Hospital Using a National Audit Tool: A Single Centre Retrospective Audit.

Identifying opportunities to safely reduce antibiotic prescribing is necessary for prescribers and antibiotic stewardship teams to minimise unwarranted antibiotic use. We aimed to quantify excess antibiotic use in General Surgery. We retrospectively audited the antibiotic prescribing for patients discharged from the General Surgery specialty in an acute hospital in the south-west of England for one month using an audit tool developed by Public Health England. The appropriateness of prescribing was determined for each patient at three antibiotic decision time-points: at initiation, the pre-72-hour antibiotic review, and treatment duration. Two infection specialists and a general surgeon reviewed each patient. Indication and excess days of therapy (DOTs) were calculated at each decision time-point and expressed as a proportion of total DOTs. Eighty-six patients were prescribed 1162 DOTs; 192 (16.5%) excess DOTs were prescribed in 38 patients (44%), with zero excess days identified in the remaining 48 patients (56%). Seventy-five of 192 (39%) excess DOTs occurred at initiation; 55/192 (29%) after the pre-72-hour antibiotic review; and 62/192 (32%) due to protracted antibiotic courses. There was concordance between the general surgeon and infection specialist for most apportioned excess DOTs. However, the surgeon apportioned fewer excess DOTs 160/1162 (13.8%). Overall IV antibiotics accounted for 53.4% of total DOTs. Seventy-two of 86 (83.7%) patients received 620 intravenous DOTs; of these, 79 (12.7%) IV DOTS were unnecessary. We have identified excess antibiotic prescribing in General surgery with comparable excess DOTs at all three time-points.

A clinical, molecular genetics and pathological study of a FTDP-17 family with a heterozygous splicing variant c.823-10G>T at the intron 9/exon 10 of the MAPT gene.

We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3' splice site.

Developing electronic learning to deliver MR safety training in a radiotherapy department.

INTRODUCTION/BACKGROUND: Magnetic Resonance Imaging (MRI) is used in radiotherapy planning, and increasingly in on-treatment guidance. The potential for the MR environment to be hazardous, without stringent safe working practices, is real. Guidance suggests all workers in MRI undergo annual safety training. To facilitate a tangible MR safety program, an electronic learning module was created and evaluated. METHODS: An existing presentation, normally delivered face-to-face, was modified and questions added to test knowledge. The module was delivered and feedback collected, together with answers to the questions, over three phases to ensure deliverability, clarity, and robustness. These comprised an initial pilot phase for non-MR personnel, an evaluation phase for staff renewing annual MR safety training, and finally for new therapeutic radiographer graduates, a test-retest methodology. RESULTS: Seven participants took part in the initial pilot phase, followed by thirty-one in the evaluation phase. Participants included radiographers (therapeutic and diagnostic), play specialists, clinical oncologists and anaesthetists, physicists and nursing staff. Within the evaluation group, 74.2% achieved a score >80%. Incorrect responses were principally related to questions regarding expected levels of responsibility and working practices, rather than the physics of high magnetic field strengths. The test-retest phase (n = 5) followed. Mean scores prior to learning were 59%, improving to 79% following learning, with the weakest sections mirroring those highlighted within the evaluation phase. DISCUSSION: Transferring MR safety training into an electronic format has provided a standardised, tangible tool that provides evidence of compliance with recommended guidance. CONCLUSIONS: This work illustrates the transition of MR safety learning for radiotherapy staff from passive presentation, to an interactive teaching methodology. The e-learning module has now been implemented within the department.

Magnet Fracture within a Magnetically Controlled Growing Rod: A Case Report of a New Mechanism of Failure.

INTRODUCTION: Magnetically controlled growing rods (MCGRs) have been widely adopted in the management of early-onset scoliosis since they were first described in 2012. Recent reports have highlighted concerns around their safety. To date, little is understood about the risk factors and modes of failure in these devices. CASE REPORT: We report a novel mechanism of device failure in a 14-year-old patient following multiple revisions of MCGRs.Clinically, there was no evidence of device failure and the MCGRs appeared radiologically intact. Explantation analysis revealed multiple compromised/non-functional components. A previously undocumented phenomenon of complete magnet fracture was also seen. CONCLUSION: The absence of clinical or radiological features of device failure in this case makes the findings of great concern. Given the relative paucity of high-quality evidence surrounding the use of MCGRs, we support calls for urgent comparative studies and further investigation of risk factors for device failure.

Development and validation of two clinical prediction models to inform clinical decision-making for lumbar spinal fusion surgery for degenerative disorders and rehabilitation following surgery: protocol for a prospective observational study.

INTRODUCTION: Potential predictors of poor outcome will be measured at baseline: (1) preoperatively to develop a clinical prediction model to predict which patients are likely to have favourable outcome following lumbar spinal fusion surgery (LSFS) and (2) postoperatively to predict which patients are likely to have favourable long-term outcomes (to inform rehabilitation). METHODS AND ANALYSIS: Prospective observational study with a defined episode inception of the point of surgery. Electronic data will be collected through the British Spine Registry and will include patient-reported outcome measures (eg, Fear-Avoidance Beliefs Questionnaire) and data items (eg, smoking status). Consecutive patients (≥18 years) undergoing LSFS for back and/or leg pain of degenerative cause will be recruited. EXCLUSION CRITERIA: LSFS for spinal fracture, inflammatory disease, malignancy, infection, deformity and revision surgery. 1000 participants will be recruited (n=600 prediction model development, n=400 internal validation derived model; planning 10 events per candidate prognostic factor). The outcome being predicted is an individual's absolute risk of poor outcome (disability and pain) at 6 weeks (objective 1) and 12 months postsurgery (objective 2). Disability and pain will be measured using the Oswestry Disability Index (ODI), and severity of pain in the previous week with a Numerical Rating Scale (NRS 0-10), respectively. Good outcome is defined as a change of 1.7 on the NRS for pain, and a change of 14.3 on the ODI. Both linear and logistic (to dichotomise outcome into low and high risk) multivariable regression models will be fitted and mean differences or ORs for each candidate predictive factor reported. Internal validation of the derived model will use a further set of British Spine Registry data. External validation will be geographical using two spinal registries in The Netherlands and Switzerland. ETHICS AND DISSEMINATION: Ethical approval (University of Birmingham ERN_17-0446A). Dissemination through peer-reviewed journals and conferences.

Incomplete cauda equina syndrome secondary to haemorrhage within a Tarlov cyst.

Sacral perineural (Tarlov) cysts are benign, cerebrospinal fluid containing lesions of the spinal nerve root sheath. They are usually asymptomatic; however, a small proportion have the potential to cause compression of nerve roots and/or the cauda equina.We report a case of a 61-year-old man who presented with acute onset back pain associated with bilateral radiculopathy. Between referral and consultation, the patient developed urinary dysfunction which resolved spontaneously.MRI revealed haemorrhage within a Tarlov cyst, resulting in compression of the cauda equina. Due to the considerable clinical improvement at the time of consultation, surgical decompression of the cyst was not considered to be indicated.An interval MRI scan 8 weeks later demonstrated that the haemorrhage within the perineural cyst had spontaneously resolved and the patient remained asymptomatic at 5-year follow-up.

Recommendations for Lengthening of Magnetically Controlled Growing Rods in Children With Pacemakers.

PURPOSE OF THE STUDY: Pacemakers are currently identified as a contraindication for the use of magnetic growth rods (MGRs). This arises from concern that magnetic fields generated by the MGR external remote controller (ERC) during lengthening procedures may induce pacemaker dysfunction. We investigated (1) whether MGR lengthening affects pacemaker function, and (2) if the magnetic field of a pacemaker affects MGR lengthening. METHODS: MGRs were tested in conjunction with an magnetic resonance imaging-compatible pacemaker, which was connected to a virtual patient under continuous cardiac monitoring. To determine whether pacemaker function was affected during MGR lengthening, the electrocardiogram trace was monitored for arrhythmias, whereas an ERC was applied to lengthen the MGRs at varying distances from the pacemaker. To investigate if MGR lengthening was affected by the presence of a pacemaker, at the start and end of the experiment, the ability of the rods to fully elongate and shorten was tested to check for conservation of function. RESULTS: When the pacemaker was in normal mode, <16 cm away from the activated ERC during MGR lengthening, pacemaker function was affected by the ERC's magnetic forces. At this distance, prophylactically switching the pacemaker to tonic mode before lengthening prevented occurrence of inappropriate pacing discharges. No deleterious effect of the pacemaker's magnetic field on the MGR lengthening mechanism was identified. CONCLUSIONS: Magnetic resonance imaging-compatible pacemakers appear safe for concomitant use with MGRs, provided a pacemaker technician prophylactically switches the pacemaker to tonic function before outpatient lengthening procedures. CLINICAL RELEVANCE: This experiment was designed to provide the first safety information on MGR lengthening in children with pacemakers. Although currently a rare clinical scenario, with increasing use of MGRs, this clinical scenario may arise more frequently in the future.

Halting of Caspase Activity Protects Tau from MC1-Conformational Change and Aggregation.

Intracellular neurofibrillary tangles (NFTs) are the hallmark of Alzheimer's disease and other tauopathies in which tau, a microtubule-associated protein, loses its ability to stabilize microtubules. Several post-translational modifications including phosphorylation and truncation increase tau's propensity to aggregate thus forming NFTs; however, the mechanisms underlying tau conformational change and aggregation still remain to be defined. Caspase activation and subsequent proteolytic cleavage of tau is thought to be a potential trigger of this disease-related pathological conformation. The aim of this work was to investigate the link between caspase activation and a disease-related conformational change of tau in a neuroblastoma cell-based model of spontaneous tau aggregation. We demonstrated that caspase induction initiates proteolytic cleavage of tau and generation of conformationally altered and aggregated tau recognized by the MC1 conformational antibody. Most importantly, these events were shown to be attenuated with caspase inhibitors. This implies that therapeutics aimed at inhibiting caspase-mediated tau cleavage may prove beneficial in slowing cleavage and aggregation, thus potentially halting tau pathology and disease progression.

Specific calpain inhibition by calpastatin prevents tauopathy and neurodegeneration and restores normal lifespan in tau P301L mice.

Tau pathogenicity in Alzheimer's disease and other tauopathies is thought to involve the generation of hyperphosphorylated, truncated, and oligomeric tau species with enhanced neurotoxicity, although the generative mechanisms and the implications for disease therapy are not well understood. Here, we report a striking rescue from mutant tau toxicity in the JNPL3 mouse model of tauopathy. We show that pathological activation of calpains gives rise to a range of potentially toxic forms of tau, directly, and by activating cdk5. Calpain overactivation in brains of these mice is accelerated as a result of the marked depletion of the endogenous calpain inhibitor, calpastatin. When levels of this inhibitor are restored in neurons of JNPL3 mice by overexpressing calpastatin, tauopathy is prevented, including calpain-mediated breakdown of cytoskeletal proteins, cdk5 activation, tau hyperphosphorylation, formation of potentially neurotoxic tau fragments by either calpain or caspase-3, and tau oligomerization. Calpastatin overexpression also prevents loss of motor axons, delays disease onset, and extends survival of JNPL3 mice by 3 months to within the range of normal lifespan. Our findings support the therapeutic promise of highly specific calpain inhibition in the treatment of tauopathies and other neurodegenerative states.

SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia.

Idiopathic basal ganglia calcification (IBGC) is characterized by bilateral calcification of the basal ganglia associated with a spectrum of neuropsychiatric and motor syndromes. In this study, we set out to determine the frequency of the recently identified IBGC gene SLC20A2 in 27 IBGC cases from the Mayo Clinic Florida Brain Bank using both Sanger sequencing and TaqMan copy number analysis to cover the complete spectrum of possible mutations. We identified SLC20A2 pathogenic mutations in two of the 27 cases of IBGC (7 %). Sequencing analysis identified a p.S113* nonsense mutation in SLC20A2 in one case. TaqMan copy number analysis of SLC20A2 further revealed a genomic deletion in a second case, which was part of a large previously reported Canadian IBGC family with dystonia. Subsequent whole-genome sequencing in this family revealed a 563,256-bp genomic deletion with precise breakpoints on chromosome 8 affecting multiple genes including SLC20A2 and the known dystonia-related gene THAP1. The deletion co-segregated with disease in all family members. The deletion of THAP1 in addition to SLC20A2 in the Canadian IBGC family may contribute to the severe and early onset dystonia in this family. The identification of an SLC20A2 genomic deletion in a familial form of IBGC demonstrates that reduced SLC20A2 in the absence of mutant protein is sufficient to cause neurodegeneration and that previously reported SLC20A2 mutation frequencies may be underestimated.

An unbiased approach to identifying tau kinases that phosphorylate tau at sites associated with Alzheimer disease.

Neurofibrillary tangles, one of the hallmarks of Alzheimer disease (AD), are composed of paired helical filaments of abnormally hyperphosphorylated tau. The accumulation of these proteinaceous aggregates in AD correlates with synaptic loss and severity of dementia. Identifying the kinases involved in the pathological phosphorylation of tau may identify novel targets for AD. We used an unbiased approach to study the effect of 352 human kinases on their ability to phosphorylate tau at epitopes associated with AD. The kinases were overexpressed together with the longest form of human tau in human neuroblastoma cells. Levels of total and phosphorylated tau (epitopes Ser(P)-202, Thr(P)-231, Ser(P)-235, and Ser(P)-396/404) were measured in cell lysates using AlphaScreen assays. GSK3α, GSK3ß, and MAPK13 were found to be the most active tau kinases, phosphorylating tau at all four epitopes. We further dissected the effects of GSK3α and GSK3ß using pharmacological and genetic tools in hTau primary cortical neurons. Pathway analysis of the kinases identified in the screen suggested mechanisms for regulation of total tau levels and tau phosphorylation; for example, kinases that affect total tau levels do so by inhibition or activation of translation. A network fishing approach with the kinase hits identified other key molecules putatively involved in tau phosphorylation pathways, including the G-protein signaling through the Ras family of GTPases (MAPK family) pathway. The findings identify novel tau kinases and novel pathways that may be relevant for AD and other tauopathies.

Erect radiographs to assess clinical instability in patients with blunt cervical spine trauma.

BACKGROUND: Computed tomography (CT) and magnetic resonance imaging (MRI) are sensitive modalities for the assessment of the spine, but certain injuries remain poorly assessed with supine radiographs. We describe four cases in which cervical spine injuries were proven as unstable with erect radiographs after being previously evaluated with supine radiographs and CT scans. METHODS: A retrospective review of medical records and images was used to identify four patients who presented to a teaching hospital from April to December 2010 with unstable cervical spine injuries that were only demonstrated on erect radiographs. RESULTS: All four patients sustained either C4-C5 or C5-C6 injuries. Prior to diagnosis, each had been evaluated with supine radiographs that did not demonstrate instability. Computed tomography identified the osseous injuries that were present but did not provide suitable assessment of stability. Three patients successfully underwent anterior cervical discectomy and fusion. The fourth was managed with a Halo jacket because of major comorbidities. CONCLUSIONS: Despite major advances in imaging, these cases highlight the importance of physiological loading and radiographs. The controlled use of erect radiographs to test for clinical instability in patients with cervical spine injuries should be considered except in cases in which instability is already evident on other imaging modalities and/or surgical treatment is already indicated.

Progranulin is a chemoattractant for microglia and stimulates their endocytic activity.

Mutations resulting in progranulin haploinsufficiency cause disease in patients with a subset of frontotemporal lobar degeneration; however, the biological functions of progranulin in the brain remain unknown. To address this subject, the present study initially assessed changes in gene expression and cytokine secretion in rat primary cortical neurons treated with progranulin. Molecular pathways enriched in the progranulin gene set included cell adhesion and cell motility pathways and pathways involved in growth and development. Secretion of cytokines and several chemokines linked to chemoattraction but not inflammation were also increased from progranulin-treated primary neurons. Therefore, whether progranulin is involved in recruitment of immune cells in the brain was investigated. Localized lentiviral expression of progranulin in C57BL/6 mice resulted in an increase of Iba1-positive microglia around the injection site. Moreover, progranulin alone was sufficient to promote migration of primary mouse microglia in vitro. Primary microglia and C4B8 cells demonstrated more endocytosis of amyloid ß1-42 when treated with progranulin. These data demonstrate that progranulin acts as a chemoattractant in the brain to recruit or activate microglia and can increase endocytosis of extracellular peptides such as amyloid ß.

Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging.

Progranulin (PGRN) is involved in wound repair, inflammation, and tumor formation, but its function in the central nervous system is unknown. Roles in development, sexual differentiation, and long-term neuronal survival have been suggested. Mutations in the GRN gene resulting in partial loss of the encoded PGRN protein cause frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions. We sought to understand the neuropathological consequences of loss of PGRN function throughout the lifespan of GRN-deficient ((-/+) and (-/-)) mice. An aged series of GRN-deficient and wild-type mice were compared by histology, immunohistochemistry, and electron microscopy. Although GRN-deficient mice were viable, GRN(-/-) mice were produced at lower than predicted frequency. Neuropathologically, GRN(-/+) were indistinguishable from controls; however, GRN(-/-) mice developed age-associated, abnormal intraneuronal ubiquitin-positive autofluorescent lipofuscin. Lipofuscin was noted in aged GRN(+/+) mice at levels comparable with those of young GRN(-/-) mice. GRN(-/-) mice developed microgliosis, astrogliosis, and tissue vacuolation, with focal neuronal loss and severe gliosis apparent in the oldest GRN(-/-) mice. Although no overt frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions type- or TAR DNA binding protein-43-positive lesions were observed, robust lipofuscinosis and ubiquitination in GRN(-/-) mice is strikingly similar to changes associated with aging and cellular decline in humans and animal models. Our data suggests that PGRN plays a key role in maintaining neuronal function during aging and supports the notion that PGRN is a trophic factor essential for long-term neuronal survival.

High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation.

BACKGROUND: Neurofibrillary tangles (NFT), a cardinal neuropathological feature of Alzheimer's disease (AD) that is highly correlated with synaptic loss and dementia severity, appear to be partly attributable to increased phosphorylation of the microtubule stabilizing protein tau at certain AD-related residues. Identifying the kinases involved in the pathologic phosphorylation of tau may provide targets at which to aim new AD-modifying treatments. RESULTS: We report results from a screen of 572 kinases in the human genome for effects on tau hyperphosphorylation using a loss of function, high-throughput RNAi approach. We confirm effects of three kinases from this screen, the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2), the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), and the A-kinase anchor protein 13 (AKAP13) on tau phosphorylation at the 12E8 epitope (serine 262/serine 356). We provide evidence that EIF2AK2 effects may result from effects on tau protein expression, whereas DYRK1A and AKAP13 are likely more specifically involved in tau phosphorylation pathways. CONCLUSIONS: These findings identify novel kinases that phosphorylate tau protein and provide a valuable reference data set describing the kinases involved in phosphorylating tau at an AD-relevant epitope.

Mimicking aspects of frontotemporal lobar degeneration and Lou Gehrig's disease in rats via TDP-43 overexpression.

Since the discovery of neuropathological lesions made of TDP-43 and ubiquitin proteins in cases of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), there is a burst of effort on finding related familial mutations and developing animal models. We used an adeno-associated virus (AAV) vector for human TDP-43 expression targeted to the substantia nigra (SN) of rats. Though TDP-43 was expressed mainly in neuronal nuclei as expected, it was also expressed in the cytoplasm, and dotted along the plasma membrane of neurons. Cytoplasmic staining was both diffuse and granular, indicative of preinclusion lesions, over 4 weeks. Ubiquitin deposited in the cytoplasm, specifically in the TDP-43 group, and staining for microglia was increased dose-dependently by 1-2 logs in the TDP-43 group, while neurons were selectively obliterated. Neuronal death induced by TDP-43 was pyknotic and apoptotic. TDP-43 gene transfer caused loss of dopaminergic neurons in the SN and their axons in the striatum. Behavioral motor dysfunction resulted after TDP-43 gene transfer that was vector dose-dependent and progressive over time. The cytoplasmic expression, ubiquitination, and neurodegeneration mimicked features of the TDP-43 diseases, and the gliosis, apoptosis, and motor impairment may also be relevant to TDP-43 disease forms involving nigrostriatal degeneration.