Committee on High-quality Alzheimer's Disease Studies (CHADS) consensus report.

BACKGROUND: Consensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials. METHODS: An ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations. RESULTS: Consensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk-benefit disclosure as part of the consent process, and the requirement to disseminate and/or publish trial results even if the study is negative. CONCLUSIONS: This consensus guidance should prove useful for the protocol development and conduct of clinical trials, and may further provide a platform for the development of education materials that may help guide appropriate clinical trial participation decisions for potential trial participants and the general public.

The Longitudinal Early-onset Alzheimer's Disease Study (LEADS): Framework and methodology.

Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aß)-positive EOAD, 200 Aß-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18 F]Florbetaben and [18 F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.

Validation of online functional measures in cognitively impaired older adults.

INTRODUCTION: Assessment of functional status is associated with risk of cognitive decline and diagnosis of dementia, and can be assessed by participants and study partners (SPs). METHODS: In 770 older adults enrolled in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study and the online Brain Health Registry (BHR), we estimated associations between online assessments and clinical variables related to Alzheimer's disease (AD) risk. RESULTS: Worse online learning scores and SP-reported functional decline were associated with higher probability of AD dementia diagnosis and poor in-clinic cognitive assessment, and with higher odds of amyloid beta (Aß) positivity when combined with participants' report of less decline. SP report of functional decline conferred predictive value independent of online cognitive assessments. Participants underreported decline compared to SPs. DISCUSSION: The results support the validity of online assessments and their greater utilization in healthcare and research settings. Online SP-reported functional decline is an indicator of dementia and AD risk.

Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need.

Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

Patient and Caregiver Assessment of the Benefits From the Clinical Use of Amyloid PET Imaging.

INTRODUCTION: Few studies to date have explored patient and caregiver views on the clinical use of amyloid positron emission tomography (PET). METHODS: A 7-item questionnaire assessing patient and caregiver views (510 total respondents) toward amyloid PET imaging was advertised broadly through alz.org/trialmatch. RESULTS: We received 510 unique responses from 48 US states, 2 Canadian provinces, the Dominican Republic, and Greece. Both patients and caregivers indicated that they would want to receive amyloid imaging if offered the opportunity. Over 88% of respondents had a positive response (∼10% with neutral and 2% with negative responses) to whether amyloid PET should be offered routinely and be reimbursed. Such information was felt to be useful for long-term legal, financial, and health care planning. Respondents identifying with early age cognitive decline (younger than 65 y) were more likely to explore options for disability insurance (P=0.03). Responders from the Midwest were more likely to utilize information from amyloid imaging for legal planning (P=0.02), disability insurance (P=0.02), and life insurance (P=0.04) than other US regions. DISCUSSION: Patients and caregivers supported the use of amyloid PET imaging in clinical practice and felt that the information would provide significant benefits particularly in terms of future planning.

2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease.

With increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long-term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations.

Immune cell-mediated neuroprotection is independent of estrogen action through estrogen receptor-alpha.

It has been well documented that both estrogen and immune cells (CD4+ T cells) mediate neuroprotection in the mouse facial nerve axotomy model. Estrogen has been shown to play an important role in regulating the immune response. However, it is unclear whether immune cell-mediated neuroprotection is dependent on estrogen signaling. In this study, using FACS staining, we confirmed that the majority of CD4+ T cells express high levels of estrogen receptor-alpha (ERα), suggesting that CD4+ T cell-mediated neuroprotection may be modulated by estrogen signaling. We previously found that immunodeficient Rag-2KO mice showed a significant increase in axotomy-induced facial motoneuron death compared to immunocompetent wild-type mice. Therefore, we investigated axotomy-induced facial motoneuron loss in immunodeficient Rag-2KO mice that received 17ß-estradiol treatment or adoptive transfer of immune cells from mice lacking functional ERα. Our results indicate that while estradiol treatment failed to rescue facial motoneurons from axotomy-induced cell death in Rag-2KO mice, immune cells lacking ERα successfully restored facial motoneuron survival in Rag-2 KO mice to a wild-type level. Collectively, we concluded that CD4+ T cell-mediated neuroprotection is independent of estrogen action through ERα.

Neuroprotective actions of androgens on motoneurons.

Androgens have a variety of protective and therapeutic effects in both the central and peripheral nervous systems. Here we review these effects as they related specifically to spinal and cranial motoneurons. Early in development, androgens are critical for the formation of important neuromuscular sex differences, decreasing the magnitude of normally occurring cell death in select motoneuron populations. Throughout the lifespan, androgens also protect against motoneuron death caused by axonal injury. Surviving motoneurons also display regressive changes to their neurites as a result of both direct axonal injury and loss of neighboring motoneurons. Androgen treatment enhances the ability of motoneurons to recover from these regressive changes and regenerate both axons and dendrites, restoring normal neuromuscular function. Androgens exert these protective effects by acting through a variety of molecular pathways. Recent work has begun to examine how androgen treatment can interact with other treatment strategies in promoting recovery from motoneuron injury.

Androgen regulates neuritin mRNA levels in an in vivo model of steroid-enhanced peripheral nerve regeneration.

Following crush injury to the facial nerve in Syrian hamsters, treatment with androgens enhances axonal regeneration rates and decreases time to recovery. It has been demonstrated in vitro that the ability of androgen to enhance neurite outgrowth in motoneurons is dependent on neuritin-a protein that is involved in the re-establisment of neuronal connectivity following traumatic damage to the central nervous system and that is under the control of several neurotrophic and neuroregenerative factors--and we have hypothesized that neuritin is a mediator of the ability of androgen to increase peripheral nerve regeneration rates in vivo. Testosterone treatment of facial nerve-axotomized hamsters resulted in an approximately 300% increase in neuritin mRNA levels 2 days post-injury. Simultaneous treatment with flutamide, an androgen receptor blocker that is known to prevent androgen enhancement of nerve regeneration, abolished the ability of testosterone to upregulate neuritin mRNA levels. In a corroborative in vitro experiment, the androgen dihydrotestosterone induced an approximately 100% increase in neuritin mRNA levels in motoneuron-neuroblastoma cells transfected with androgen receptors, but not in cells without androgen receptors. These data confirm that neuritin is under the control of androgens, and suggest that neuritin is an important effector of androgen in enhancing peripheral nerve regeneration following injury. Given that neuritin has now been shown to be involved in responses to both central and peripheral injuries, and appears to be a common effector molecule for several neurotrophic and neurotherapeutic agents, understanding the neuritin pathway is an important goal for the clinical management of traumatic nervous system injuries.

Effects of single versus combinatorial treatment strategies on beta II-tubulin gene expression in axotomized hamster rubrospinal motoneurons.

PURPOSE: betaII-tubulin, a regeneration-associated gene, is upregulated in injured peripheral neurons, but significantly less so in injured central neurons. Using a hamster dorsal spinal cord injury (SCI), the ability of single versus combinatorial treatment strategies to alter betaII-tubulin mRNA expression in rubrospinal motoneurons (RSMN) was examined. We have shown that systemic testosterone propionate (TP) treatment in combination with peripheral nerve grafting into a SCI site produces a peripheral-like pattern of betaII-tubulin mRNA expression in injured RSMN. In the present study, selected single- and combinatorial-therapy strategies were tested for their ability to promote a sustained upregulation of betaII-tubulin mRNA levels in injured RSMN. METHODS: Single treatments of olfactory ensheathing cells (OEC), brain-derived neurotrophic factor (BDNF), or Schwann cells (SC) vs combinatorial treatments (SC+TP, OEC+TP, and OEC+BDNF) were administered to hamsters following a dorsal SCI. Quantitative in situ hybridization in conjunction with a betaII-tubulin cDNA probe was accomplished. RESULTS: All of the single-therapy treatments tested were able to prevent the downregulation of betaII-tubulin mRNA that occurred a week after injury alone, but only BDNF maintained high levels of betaII-tubulin mRNA. In contrast, all combinatorial treatments tested maintained the upregulation of betaII-tubulin mRNA expression in injured RSMN 1 week post-SCI. CONCLUSIONS: Targeting both intrinsic and extrinsic components of CNS injury can re-program elements of the molecular response of injured central motoneurons.

Bupivacaine increases the rate of motoneuron death following peripheral nerve injury.

BACKGROUND: Appropriate management of pain after an injury or surgical procedure has been shown to improve patient outcomes. While infrequent, nerve damage resulting from regional anesthesia can be devastating, however the mechanism remains unknown. Local anesthetics are neurotoxic yet are frequently applied to sites where peripheral nerves are regenerating. Therefore, understanding their effects on injured and growing neurons may have important implications for clinical practice. OBJECTIVE: The purpose of this study was to determine if local anesthetics exacerbate the rate of motoneuron death following axotomy. METHODS: Mice were subjected to a unilateral transection of the facial motor nerve, and either normal saline, 2% lidocaine, or 0.75% bupivacaine was placed at the injury site. Four weeks post-axotomy, percent survival was determined by comparing the number of motoneuron cell bodies on the injured side and the uninjured control side. RESULTS: The average facial motoneuron survival in the saline, lidocaine, and bupivacaine groups 4 weeks after axotomy was 80%, 78% and 35%, respectively. CONCLUSION: Our data suggest that bupivacaine exacerbates levels of cell death in injured motoneurons. It has been proposed that once a nerve is damaged, it becomes more susceptible to injury elsewhere along the nerve. Thus, an improved understanding of the effects of local anesthetics on neuron survival and axon regeneration may lead to strategies to identify patients at higher risk for permanent neural deficits after peripheral nerve blocks and/or decrease the risk of neural deficit following peripheral nerve blocks.

Electrical stimulation and testosterone enhance recovery from recurrent laryngeal nerve crush.

OBJECTIVE: This study investigated the effects of a combinatorial treatment, consisting of a brief period of nerve electrical stimulation (ES) and systemic supraphysiologic testosterone, on functional recovery following a crush of the recurrent laryngeal nerve (RLN). STUDY DESIGN: Prospective, controlled animal study. METHODS: After a crush of the left RLN, adult male Sprague-Dawley rats were divided into four treatment groups: 1) no treatment, 2) ES, 3) testosterone propionate (TP), and 4) ES + TP. Each group was subdivided into 1, 2, 3, or 4 weeks post-operative survival time points. Groups had an n of 4- 9. Recovery of vocal fold mobility (VFM) was assessed. RESULTS: Brief ES of the proximal nerve alone or in combination with TP accelerated the initiation of functional recovery. TP administration by itself also produced increased VFM scores compared to controls, but there were no statistical differences between the ES-treated and TP-treated animals. Treatment with brief ES alone was sufficient to decrease the time required to recover complete VFM. Animals with complete VFM were seen in treatment groups as early as 1 week following injury; in the untreated group, this was not observed until at least 3 weeks post-injury, translating into a 66% decrease in time to complete recovery. CONCLUSIONS: Brief ES, alone or in combination with TP, promise to be effective therapeutic interventions for promoting regeneration following RLN injury.

Outcomes of endoscopy and computed tomography in patients with chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common disease diagnosed based on a combination of symptoms, imaging, and/or endoscopy. Computed tomography (CT) is the gold standard in diagnosis of CRS due to inherent low sensitivity of endoscopy. We sought to assess the correlation between symptoms, endoscopy, and imaging in order to reduce the number of CTs without decreasing diagnostic accuracy. METHODS: Retrospective review of a single practitioner's patients from 2008 to 2010 who presented for evaluation of CRS. Data on demographics, symptoms, and endoscopic and CT findings were collected and analyzed. Exclusion criteria included patients with prior surgery, no imaging, and those that failed to meet the 2007 CRS Task Force symptom criteria. RESULTS: A total of 244 patients met the Task Force symptom criteria. Using CT as the gold standard, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of endoscopy alone was 36%, 95%, 89%, and 55%, respectively. The number of symptoms (NOS) strongly correlated with the absence or presence of disease (p < 0.01). Incorporating NOS into a CRS diagnostic algorithm improved sensitivity and NPV of nasal endoscopy to 82% and 79% while maintaining its specificity and PPV at 82% and 84%, respectively. Applying our algorithm retrospectively would have resulted in a reduction in the number of CTs by 69%, resulting in an acceptable 10% (n = 24/244) false negative rate and 8% (n = 20/244) false positive rate. CONCLUSION: Incorporating number of symptoms in a CRS diagnostic algorithm may drastically reduce the number of CTs needed. Clinical diagnostic accuracy is enhanced with this new algorithm while significantly reducing the cost and radiation burden of CTs.

Single session of brief electrical stimulation immediately following crush injury enhances functional recovery of rat facial nerve.

Peripheral nerve injuries lead to a variety of pathological conditions, including paresis or paralysis when the injury involves motor axons. We have been studying ways to enhance the regeneration of peripheral nerves using daily electrical stimulation (ES) following a facial nerve crush injury. In our previous studies, ES was not initiated until 24 h after injury. The current experiment tested whether ES administered immediately following the crush injury would further decrease the time for complete recovery from facial paralysis. Rats received a unilateral facial nerve crush injury and an electrode was positioned on the nerve proximal to the crush site. Animals received daily 30 min sessions of ES for 1 d (day of injury only), 2 d, 4 d, 7 d, or daily until complete functional recovery. Untreated animals received no ES. Animals were observed daily for the return of facial function. Our findings demonstrated that one session of ES was as effective as daily stimulation at enhancing the recovery of most functional parameters. Therefore, the use of a single 30 min session of ES as a possible treatment strategy should be studied in human patients with paralysis as a result of acute nerve injuries.

Lateral temporal bone and parotid malignancy with facial nerve involvement.

OBJECTIVES: To review our institution's experience and outcomes in the treatment of lateral temporal bone (LTB) and parotid malignancy with facial nerve (FN) involvement. To identify risk factors for treatment failures and to clarify previously established prognostic factors for this advanced-stage disease. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care academic hospital. SUBJECTS AND METHODS: A series of 26 patients treated operatively for malignancy of the LTB and parotid gland with FN involvement were reviewed retrospectively. All patients underwent sacrifice of the FN due to intraoperative determination of nerve invasion. Demographic, historical, intraoperative, pathologic, and follow-up data were collected and analyzed to determine survival outcomes and locoregional control. Risk factor analysis was performed. RESULTS: The FN was found to be grossly involved by tumor at the stylomastoid foramen in 57.7% of patients, resulting in sacrifice more proximally in the vertical segment in 57.7%. Statistical analysis demonstrated a locoregional recurrence rate of 34.6%, with the majority of recurrence occurring within the first 2 years after surgery. The rate of distant failure was 15.4%. Kaplan-Meier and chi-square analysis showed an overall survival of 76.0%, 66.7%, 35.3%, 31.2%, and 28.6% at 1, 2, 3, 4, and 5 years, respectively. Advanced age, the presence of tumor of epithelial origin, and pathologically positive lymph nodes are significantly predictive of poor survival. CONCLUSION: Outcomes of malignancy of the LTB with FN involvement treated with primary surgical therapy compare favorably with previously published control rates, and overall prognosis for this condition is likely better than historically established.

Neuroprotective effect of testosterone treatment on motoneuron recruitment following the death of nearby motoneurons.

Motoneuron loss is a significant medical problem, capable of causing severe movement disorders or even death. We have previously shown that motoneuron death induces marked dendritic atrophy in surviving nearby motoneurons. Additionally, in quadriceps motoneurons, this atrophy is accompanied by decreases in motor nerve activity. However, treatment with testosterone partially attenuates changes in both the morphology and activation of quadriceps motoneurons. Testosterone has an even larger neuroprotective effect on the morphology of motoneurons of the spinal nucleus of the bulbocavernosus (SNB), in which testosterone treatment can completely prevent dendritic atrophy. The present experiment was performed to determine whether the greater neuroprotective effect of testosterone on SNB motoneuron morphology was accompanied by a greater neuroprotective effect on motor activation. Right side SNB motoneurons were killed by intramuscular injection of cholera toxin-conjugated saporin in adult male Sprague-Dawley rats. Animals were either given Silastic testosterone implants or left untreated. Four weeks later, left side SNB motor activation was assessed with peripheral nerve recording. The death of right side SNB motoneurons resulted in several changes in the electrophysiological response properties of surviving left side SNB motoneurons, including decreased background activity, increased response latency, increased activity duration, and decreased motoneuron recruitment. Treatment with exogenous testosterone attenuated the increase in activity duration and completely prevented the decrease in motoneuron recruitment. These data provide a functional correlate to the known protective effects of testosterone treatment on the morphology of these motoneurons, and further support a role for testosterone as a therapeutic agent in the injured nervous system.

Androgen regulation of axon growth and neurite extension in motoneurons.

Androgens act on the CNS to affect motor function through interaction with a widespread distribution of intracellular androgen receptors (AR). This review highlights our work on androgens and process outgrowth in motoneurons, both in vitro and in vivo. The actions of androgens on motoneurons involve the generation of novel neuronal interactions that are mediated by the induction of androgen-dependent neurite or axonal outgrowth. Here, we summarize the experimental evidence for the androgenic regulation of the extension and regeneration of motoneuron neurites in vitro using cultured immortalized motoneurons, and axons in vivo using the hamster facial nerve crush paradigm. We place particular emphasis on the relevance of these effects to SBMA and peripheral nerve injuries.