Cost-effectiveness of surgery for degenerative cervical myelopathy in the United Kingdom.

PURPOSE: Degenerative cervical myelopathy (DCM) is the commonest cause of adult spinal cord dysfunction worldwide, for which surgery is the mainstay of treatment. At present, there is limited literature on the costs associated with the surgical management of DCM, and none from the United Kingdom (UK). This study aimed to evaluate the cost-effectiveness of DCM surgery within the National Health Service, UK. MATERIALS AND METHODS: Incidence of DCM was identified from the Hospital Episode Statistics (HES) database for a single year using five ICD-10 diagnostic codes to represent DCM. Health Resource Group (HRG) data was used to estimate the mean incremental surgery (treatment) costs compared to non-surgical care, and the incremental effect (quality adjusted life year (QALY) gain) was based on data from a previous study. A cost per QALY value of <£30,000/QALY (GBP) was considered acceptable and cost-effective, as per the National Institute for Health and Clinical Excellence (NICE) guidance. A sensitivity analysis was undertaken (±5%, ±10% and ±20%) to account for variance in both the cost of admission and QALY gain. RESULTS: The total number of admissions for DCM in 2018 was 4,218. Mean age was 62 years, with 54% of admissions being of working age (18-65 years). The overall estimated cost of admissions for DCM was £38,871,534 for the year. The mean incremental (per patient) cost of surgical management of DCM was estimated to be £9,216 (ranged £2,358 to £9,304), with a QALY gain of 0.64, giving an estimated cost per QALY value of £14,399/QALY. Varying the QALY gain by ±20%, resulted in cost/QALY figures between £12,000 (+20%) and £17,999 (-20%). CONCLUSIONS: Surgery is estimated to be a cost-effective treatment of DCM amongst the UK population.

Factors associated with poorer outcomes for posterior lumbar decompression and or/or discectomy: an exploratory analysis of administrative data.

PURPOSE: This study aimed to identify factors associated with poorer patient outcomes for lumbar decompression and/or discectomy (PLDD). METHODS: We extracted data from the Hospital Episodes Statistics database for the 5 years from 1st April 2014 to 31st March 2019. Patients undergoing an elective one- or two-level PLDD aged ≥ 17 years and without evidence of revision surgery during the index stay were included. The primary patient outcome measure was readmission within 90 days post-discharge. RESULTS: Data for 93,813 PLDDs across 111 hospital trusts were analysed. For the primary outcome, greater age [< 40 years vs 70-79 years odds ratio (OR) 1.28 (95% confidence interval (CI) 1.14 to 1.42), < 40 years vs ≥ 80 years OR 2.01 (95% CI 1.76-2.30)], female sex [OR 1.09 (95% CI 1.02-1.16)], surgery over two spinal levels [OR 1.16 (95% CI 1.06-1.26)] and the comorbidities chronic pulmonary disease, connective tissue disease, liver disease, diabetes, hemi/paraplegia, renal disease and cancer were all associated with emergency readmission within 90 days. Other outcomes studied had a similar pattern of associations. CONCLUSIONS: A high-throughput PLDD pathway will not be suitable for all patients. Extra care should be taken for patients aged ≥ 70 years, females, patients undergoing surgery over two spinal levels and those with specific comorbidities or generalised frailty.

Trends Over Time in the Use, Carbon Footprint and Costs of Facet Joint Injections and Medial Branch Blocks to Manage Lumbar Pain in England: Retrospective Analysis of an Administrative Dataset.

STUDY DESIGN: Retrospective analysis of an administrative dataset. OBJECTIVE: This study aims to investigate changing practice over a six-year period in the use of repeated lumbar facet joint injections/medial branch blocks in England. METHODS: Patient data were extracted from the Hospital Episodes Statistics database for the period 1st April 2015 to 31st March 2021 for the index lumbar injection and for repeat lumbar injections performed within one year of the first. The exposure of interest was two injections within 180 days or three within one year. Patients aged <17 years and where the body site was listed as cervical, thoracic or sacral were excluded. RESULTS: Data were available for 134,249 patients of which, 8,922 (6.6%) had either two injections within 180 days or three injections within one year. First injections fell from 42,511 in 2015/16 to 13,368 in 2019/20 as did the number of repeat injections: 4,018 to 424 for the same period. If all years had the same carbon footprint as 2019/20, 2.8 kilotons of CO2e would have been saved over the five years, enough to power 2,575 average UK homes for 1 year. The financial cost of injections decreased from £27.6 million in 2015/16 to £7.9 million in 2019/20. CONCLUSIONS: The number of patients having repeated lumbar injections has decreased over time but has not been eliminated. More work is needed to educate patients and clinicians regarding alternative and more effective treatments.

Diagnosis of cauda equina syndrome in the emergency department.

Cauda equina syndrome (CES) is a spinal emergency that can be challenging to identify from among the many patients presenting to EDs with low back and/or radicular leg pain. This article presents a practical guide to the assessment and early management of patients with suspected CES as well as an up-to-date review of the most important studies in this area that should inform clinical practice in the ED.

Safety of Same-Day Discharge Posterior Lumbar Decompression and/or Discectomy: An Observational Study Using Administrative Data From England.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: Same-day discharge is widely used in many surgical specialities. If carefully planned, it can improve patient outcomes whilst using resources efficiently. We aimed to investigate the safety of same-day discharge following a posterior lumbar decompression and/or discectomy (PLDD). METHODS: This was a retrospective analysis of administrative data. We extracted data from the Hospital Episodes Statistics database for the 5 years from 1st April 2014 to 31st March 2019. Patients undergoing an elective one or two level PLDD aged 19-54 years during the index stay were included. The primary exposure variable was same-day discharge or post-surgery overnight stay and the primary outcome was emergency hospital readmission within 90 days post-discharge. RESULTS: Data were available for 45,814 PLDD performed across 103 hospital trusts of which 7914 (17.3%) were performed as same-day discharge. Same-day discharge rates varied from 87.7% to 0% across the 90 hospital trusts that operated on more than 50 patients during the study period. Fourteen (15.6%) trusts had same-day discharge rates above 30% and 57 (63.3%) trusts had same-day discharge rates below 10%. The odds of emergency hospital readmission within 90 days were lower for same-day discharge patients (odds ratio .72 (95% confidence interval .61 to .85). There was no difference in outcomes for patients seen at trusts with a same-day discharge rate of ≥30% compared to trusts with a same-day discharge rate of ≤10%. CONCLUSIONS: Same-day discharge low-complexity elective PLDD is safe in adult patients below the age of 55 years. There is potential for many providers to substantially increase their rates of same-day discharge.

An observational study of vertebroplasty and kyphoplasty for osteoporotic spinal fractures: utilisation and outcomes in England using an administrative dataset.

We reviewed outcomes for vertebroplasty and balloon kyphoplasty for the surgical treatment of osteoporotic spinal fracture. Our study of 5792 vertebroplasty and 3136 balloon kyphoplasty procedures conducted in England over a 7-year period found no evidence that the patient outcomes studied were poorer for vertebroplasty than for balloon kyphoplasty. PURPOSE: To investigate use, safety and functional outcomes of vertebroplasty (VP) and balloon kyphoplasty (BKP) techniques for osteoporotic spinal fracture for patients operated on within the National Health Service in England. METHODS: This was an observational analysis of administrative data. Data were extracted from the Hospital Episodes Statistics database for the period 1st April 2011 to 31st March 2018 for all VP and BKP procedures. Patients aged < 19 years, with metastatic carcinoma and undergoing other decompression procedures, were excluded. The primary outcome was repeat spinal surgery within 1 year. Secondary outcomes were 30-day emergency readmission, death within 1 year, extended hospital stay, post-procedural pain within 30 days and post-procedural haemorrhage or infection within 30 days. Multilevel, multivariable logistic regression was used to adjust for covariates. RESULTS: Data were available for 5792 VP and 3136 BKP patients operated on at 96 hospital trusts. In the 63 trusts that conducted more than 20 procedures during the study period, the proportion of procedures conducted as BKP varied from 0 to 100%. There was no difference in any of the outcomes between VP and BKP patients or between trusts performing ≥ 70% and ≤ 30% of procedures as BKP. CONCLUSIONS: With regard to the outcomes studied, there is no evidence that VP is associated with poorer outcomes than BKP.

Improving Awareness Could Transform Outcomes in Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 1].

STUDY DESIGN: Literature Review (Narrative). OBJECTIVE: To introduce the number one research priority for Degenerative Cervical Myelopathy (DCM): Raising Awareness. METHODS: Raising awareness has been recognized by AO Spine RECODE-DCM as the number one research priority. This article reviews the evidence that awareness is low, the potential drivers, and why this must be addressed. Case studies of success from other diseases are also reviewed, drawing potential parallels and opportunities for DCM. RESULTS: DCM may affect as many as 1 in 50 adults, yet few will receive a diagnosis and those that do will wait many years for it. This leads to poorer outcomes from surgery and greater disability. DCM is rarely featured in healthcare professional training programs and has received relatively little research funding (<2% of Amyotrophic Lateral Sclerosis or Multiple Sclerosis over the last 25 years). The transformation of stroke and acute coronary syndrome services, from a position of best supportive care with occasional surgery over 50 years ago, to avoidable disability today, represents transferable examples of success and potential opportunities for DCM. Central to this is raising awareness. CONCLUSION: Despite the devastating burden on the patient, recognition across research, clinical practice, and healthcare policy are limited. DCM represents a significant unmet need that must become an international public health priority.

Current surgical practice for multi-level degenerative cervical myelopathy: Findings from an international survey of spinal surgeons.

Degenerative cervical myelopathy (DCM) results from compression of the cervical spine cord as a result of age related changes in the cervical spine, and affects up to 2% of adults, leading to progressive disability. Surgical decompression is the mainstay of treatment, but there remains significant variation in surgical approaches used. This survey was conducted in order to define current practice amongst spine surgeons worldwide, as a possible prelude to further studies comparing surgical approaches. METHODS: An electronic survey was developed and piloted by the investigators using SurveyMonkey. Collected data was categorical and is presented using summary statistics. Where applicable, statistical comparisons were made using a Chi-Squared test. The level of significance for all statistical analyses was defined as p < 0.05. All analysis, including graphs was performed using R (R Studio). RESULTS: 127 surgeons, from 30 countries completed the survey; principally UK (66, 52%) and North America (15, 12%). Respondents were predominantly Neurosurgeons by training (108, 85%) of whom 84 (75%) reported Spinal Surgery as the principal part of their practice. The majority indicated they selected their surgical procedure for multi-level DCM on a case by case basis (62, 49%). Overall, a posterior approach was more popular for multi-level DCM (74, 58%). Region, speciality or annual multi-level case load did not influence this significantly. However, there was a trend for North American surgeons to be more likely to favour a posterior approach. CONCLUSIONS: A posterior approach was favoured and more commonly used to treat multi-level DCM, in an international cohort of surgeons. Posterior techniques including laminectomy, laminectomy and fusion or laminoplasty appeared to be equally popular.

Multiple injections for low back pain: What's the future?

AIMS: To examine the strength of evidence available for multiple facet joint injections (FJIs) and medial branch blocks (MBBs), and to report on the variations in the NHS England framework using the getting it right first time (GIRFT) data. METHODS: Systematic review using patient, intervention, comparison, outcome and study strategy. The literature search using Cochrane, MEDLINE and EMBASE databases using MeSH terms: lumbar spine, spinal injection and facet joint ("Appendix A"). RESULTS: Three studies were identified that investigated the efficacy of multiple FJIs or MBBs. None of these studies reported sustained positive outcomes at long-term follow-up. CONCLUSION: There is a paucity of levels I and II evidence available for the efficacy of multiple FJIs and MBBs in treating low back pain. GIRFT data show a high degree of variation in the use of multiple FJIs, which would not be supported by the literature. These slides can be retrieved under Electronic Supplementary Material.

Tackling gaps in developing life-changing treatments for dementia.

Since the G8 dementia summit in 2013, a number of initiatives have been established with the aim of facilitating the discovery of a disease-modifying treatment for dementia by 2025. This report is a summary of the findings and recommendations of a meeting titled "Tackling gaps in developing life-changing treatments for dementia", hosted by Alzheimer's Research UK in May 2018. The aim of the meeting was to identify, review, and highlight the areas in dementia research that are not currently being addressed by existing initiatives. It reflects the views of leading experts in the field of neurodegeneration research challenged with developing a strategic action plan to address these gaps and make recommendations on how to achieve the G8 dementia summit goals. The plan calls for significant advances in (1) translating newly identified genetic risk factors into a better understanding of the impacted biological processes; (2) enhanced understanding of selective neuronal resilience to inform novel drug targets; (3) facilitating robust and reproducible drug-target validation; (4) appropriate and evidence-based selection of appropriate subjects for proof-of-concept clinical trials; (5) improving approaches to assess drug-target engagement in humans; and (6) innovative approaches in conducting clinical trials if we are able to detect disease 10-15 years earlier than we currently do today.

Contact Sports as a Risk Factor for Amyotrophic Lateral Sclerosis: A Systematic Review.

STUDY DESIGN: Systematic review. INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, ultimately resulting in paralysis and death. The condition is considered to be caused by a complex interaction between environmental and genetic factors. Although vast genetic research has deciphered many of the molecular factors in ALS pathogenesis, the environmental factors have remained largely unknown. Recent evidence suggests that participation in certain types of sporting activities are associated with increased risk for ALS. OBJECTIVE: To test the hypothesis that competitive sports at the highest level that involve repetitive concussive head and cervical spinal trauma result in an increased risk of ALS compared with the general population or nonsport controls. METHODS: Electronic databases from inception to November 22, 2017 and reference lists of key articles were searched to identify studies meeting inclusion criteria. RESULTS: Sixteen studies met the inclusion criteria. Sports assessed (professional or nonprofessional) included soccer (n = 5), American football (n = 2), basketball (n = 1), cycling (n = 1), marathon or triathlon (n = 1), skating (n = 1), and general sports not specified (n = 11). Soccer and American football were considered sports involving repetitive concussive head and cervical spinal trauma. Professional sports prone to repetitive concussive head and cervical spinal trauma were associated with substantially greater effects (pooled rate ratio [RR] 8.52, 95% CI 5.18-14.0) compared with (a) nonprofessional sports prone to repetitive concussive head and cervical spinal trauma (pooled RR 0.60, 95% CI 0.12-3.06); (b) professional sports not prone to repetitive head and neck trauma (pooled RR 1.35, 95% CI 0.67-2.71); or (c) nonprofessional sports not prone to repetitive concussive head and cervical spinal trauma (pooled RR 1.17, 95% CI 0.79-1.71). CONCLUSIONS: Our review suggests that increased susceptibility to ALS is significantly and independently associated with 2 factors: professional sports and sports prone to repetitive concussive head and cervical spinal trauma. Their combination resulted in an additive effect, further increasing this association to ALS.

Correction to: Can spinal surgery in England be saved from litigation: a review of 978 clinical negligence claims against the NHS.

Unfortunately, the first author name was incorrectly published in the original publication. The complete correct name is given as below.

Can spinal surgery in England be saved from litigation: a review of 978 clinical negligence claims against the NHS.

PURPOSE: The aim of this study is to evaluate the true incidence of all clinical negligence claims against spinal surgery performed by orthopaedic spinal surgeons and neurosurgeons in the National Health Service (NHS) in England, including both open and closed claims. METHODS: This study was a retrospective review of 978 clinical negligence claims held by NHS Resolution against spinal surgery cases identified from claims against 'Neurosurgery' and 'Orthopaedic Surgery'. This category included all emergency, trauma and elective work and all open and closed cases without exclusion between April 2012 and April 2017. RESULTS: Clinical negligence claims in spinal surgery were estimated to cost £535.5 million over this five-year period. There is a trend of both increasing volume and estimated costs of claims. The most common causes for claims were 'judgement/timing' (512 claims, 52.35%), 'interpretation of results/clinical picture' (255 claims, 26.07%), 'unsatisfactory outcome to surgery' (192 claims, 19.63%), 'fail to warn/informed consent' (80 claims, 8.13%) and 'never events' including 'wrong site surgery' or 'retained instrument post-operation' (26 claims, 2.66%). A sub-analysis of 3 years including 574 claims revealed the most prevalent pathologies were iatrogenic nerve damage (132 claims, 23.00%), cauda equina syndrome (CES) (131 claims, 22.82%), inadequate decompression (91 claims, 15.85%), iatrogenic cord damage (72 claims, 12.54%), and infection (51 claims, 8.89%). CONCLUSIONS: The volume and costs of clinical negligence claims is threatening the future of spinal surgery. If spinal surgery is to continue to serve the patients who need it, most thorough investigation, implementation and sharing of lessons learned from litigation claims must be systematically carried out. These slides can be retrieved under Electronic Supplementary Material.

Do Growing Rods for Idiopathic Early Onset Scoliosis Improve Activity and Participation for Children?

OBJECTIVE: To investigate whether growing rod surgery for children with progressive idiopathic early onset scoliosis (EOS) effects activity and participation, and investigate factors that may affect this. STUDY DESIGN: Multicenter retrospective cohort study using prospectively collected data on 60 children with idiopathic EOS and significant scoliosis (defined as a Cobb angle >40°). Thirty underwent brace treatment, and 30, growth rod surgery. Questionnaire and radiographic data were recorded at 1 year. The validated Activities Scale for Kids performance version (ASKp) questionnaire was used to measure activity and participation. RESULTS: In the brace group, Cobb angle increased from 60° to 68°. There was no change in ASKp score. In the operative group, Cobb angle decreased from 67° to 45°. ASKp decreased from 91 to 88 (P < .01). Presence of spinal pain correlated with greater reduction in activity and participation scores in both groups, as did occurrence of complications in the operative group (P < .05). Both treatments permitted growth of the immature spine. CONCLUSIONS: In children with significant idiopathic EOS (Cobb angle>40°), growth rod surgery was associated with a reduction in activity and participation and Cobb angle, whereas brace treatment was associated with an increase in Cobb angle and no change in activity and participation. Pain was the most important factor affecting activity and participation in both groups.

Alternative technique in atypical spinal decompression: the use of the ultrasonic scalpel in paediatric achondroplasia.

Spinal stenosis can be a very disabling condition. Surgical decompression carries a risk of dural tear and neural injury, which is increased in patients with severe stenosis or an atypical anatomy. We present an unusual case of symptomatic stenosis secondary to achondroplasia presenting in a paediatric patient, and highlight a new surgical technique used to minimise the risk of dural and neural injury during decompression.

Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice.

Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43PrP) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43PrP mice. Finally, TDP-43PrP mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity.

Alzheimer disease-like phenotype associated with the c.154delA mutation in progranulin.

OBJECTIVE: To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), with emphasis on the unique clinical features in this kindred. DESIGN: Antemortem and postmortem characterization of a kindred with a familial neurodegenerative disorder. SETTING: Multispecialty group academic medical center. PATIENTS: Affected members of a kindred with dementia with or without parkinsonism associated with a unique mutation in PGRN. MAIN OUTCOME MEASURE: Genotype-phenotype correlation. RESULTS: Of 10 affected individuals identified, 6 presented with early amnestic symptoms which resulted in initial diagnoses of Alzheimer disease or amnestic mild cognitive impairment. Some individuals presented with features characteristic of frontotemporal dementia. Mean age at onset was substantially younger in generation III (75.8 years; range, 69-80 years) than in generation II (60.7 years; range, 55-66 years). The pattern of cerebral atrophy varied widely in the affected individuals. Neuropathologic features in 6 individuals included frontotemporal lobar degeneration with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U with NII). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), which caused a frameshift (p.Thr52HisfsX2) and, therefore, creation of a premature termination codon and a likely null allele. CONCLUSIONS: In this large kindred, most affected individuals had clinical presentations that resembled Alzheimer disease or amnestic mild cognitive impairment associated with a mutation in PGRN and underlying FTLD-U with NII neuropathologic abnormalities. This finding is in distinct contrast to previously reported kindreds, in which clinical presentations have typically been within the spectrum of FTLD. The basis for the large difference in age at onset between generations requires further study.

Oral treatment with a gamma-secretase inhibitor improves long-term potentiation in a mouse model of Alzheimer's disease.

The beta-amyloid peptide (Abeta) is thought to play a critical role in the pathophysiology of Alzheimer's disease (AD). To study the effects of Abeta on the brain, transgenic mouse models have been developed that express high levels of Abeta. These mice show some features of AD, including amyloid plaques and mild cognitive impairment, but not others such as progressive neurodegeneration. We investigated the age-dependent effects of Abeta on synaptic physiology in Tg2576 mice that express human Abeta. We report that both basal synaptic activity and long-term potentiation (LTP), as measured in the CA1 region of the hippocampus, were compromised by 7 months of age before plaque deposition. Despite a persistent increase in Abeta levels with age, LTP recovered in 14-month-old mice, with no further loss of basal activity compared with activity measured in 7-month-old mice. Previous work has shown that inhibitors of gamma-secretase, an enzyme critical for Abeta synthesis, can significantly reduce Abeta production and plaque formation in Tg2576 mice. Our data demonstrate that 7-month-old Tg2576 mice treated with an orally available gamma-secretase inhibitor showed a significant improvement in synaptic function and plasticity within days, and the effect was correlated with the extent and duration of Abeta reduction. These results indicate that recovery from Abeta-mediated synaptotoxicity can occur rapidly with Abeta-lowering therapies. These findings highlight some of the strengths and limitations of using Abeta-overexpressing mouse models for Alzheimer's drug discovery.

Overexpression of wild-type murine tau results in progressive tauopathy and neurodegeneration.

Here, we describe the generation and characterization of a novel tau transgenic mouse model (mTau) that overexpresses wild-type murine tau protein by twofold compared with endogenous levels. Transgenic tau expression was driven by a BAC transgene containing the entire wild-type mouse tau locus, including the endogenous promoter and the regulatory elements associated with the tau gene. The mTau model therefore differs from other tau models in that regulation of the genomic mouse transgene mimics that of the endogenous gene, including normal exon splicing regulation. Biochemical data from the mTau mice demonstrated that modest elevation of mouse tau leads to tau hyperphosphorylation at multiple pathologically relevant epitopes and accumulation of sarkosyl-insoluble tau. The mTau mice show a progressive increase in hyperphosphorylated tau pathology with age up to 15 to 18 months, which is accompanied by gliosis and vacuolization. In contrast, older mice show a decrease in tau pathology levels, which may represent hippocampal neuronal loss occurring in this wild-type model. Collectively, these results describe a novel model of tauopathy that develops pathological changes reminiscent of early stage Alzheimer's disease and other related neurodegenerative diseases, achieved without overexpression of a mutant human tau transgene. This model will provide an important tool for understanding the early events leading to the development of tau pathology and a model for analysis of potential therapeutic targets for sporadic tauopathies.