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Recently, computational drug repurposing has emerged as a promising method for identifying new pharmaceutical interventions (PI) for Alzheimer’s Disease (AD). Non-pharmaceutical interventions (NPI), such as Vitamin E and Music therapy, have great potential to improve cognitive function and slow the progression of AD, but have largely been unexplored. This study predicts novel NPIs for AD through link prediction on our developed biomedical knowledge graph. We constructed a comprehensive knowledge graph containing AD concepts and various potential interventions, called ADInt, by integrating a dietary supplement domain knowledge graph, SuppKG, with semantic relations from SemMedDB database. Four knowledge graph embedding models (TransE, RotatE, DistMult and ComplEX) and two graph convolutional network models (R-GCN and CompGCN) were compared to learn the representation of ADInt. R-GCN outperformed other models by evaluating on the time slice test set and the clinical trial test set and was used to generate the score tables of the link prediction task. Discovery patterns were applied to generate mechanism pathways for high scoring triples. Our ADInt had 162,213 nodes and 1,017,319 edges. The graph convolutional network model, R-GCN, performed best in both the Time Slicing test set (MR = 7.099, MRR = 0.5007, Hits@1 = 0.4112, Hits@3 = 0.5058, Hits@10 = 0.6804) and the Clinical Trials test set (MR = 1.731, MRR = 0.8582, Hits@1 = 0.7906, Hits@3 = 0.9033, Hits@10 = 0.9848). Among high scoring triples in the link prediction results, we found the plausible mechanism pathways of (Photodynamic therapy, PREVENTS, Alzheimer’s Disease) and (Choerospondias axillaris, PREVENTS, Alzheimer’s Disease) by discovery patterns and discussed them further. In conclusion, we presented a novel methodology to extend an existing knowledge graph and discover NPIs (dietary supplements (DS) and complementary and integrative health (CIH)) for AD. We used discovery patterns to find mechanisms for predicted triples to solve the poor interpretability of artificial neural networks. Our method can potentially be applied to other clinical problems, such as discovering drug adverse reactions and drug-drug interactions.

ObjectiveThe clinical phenotype of the rare behavioural variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination.MethodsFor the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a ‘typical’ memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7).ResultsIndividual regional W-scores ≥1.96 (corresponding to p0.05).ConclusionsBoth in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

OBJECTIVE: To determine whether clinically normal older adults with remote, mild traumatic brain injury (mTBI) show evidence of higher cortical Aβ burden. PARTICIPANTS AND MEASUREMENTS: We studied 134 clinically normal older adults (age 74.1±6.8 years, 59.7% female, 85.8% white) who underwent Aβ positron emission tomography (Aβ-PET) and who completed the Ohio State University Traumatic Brain Injury Identification questionnaire. We limited participants to those reporting injuries classified as mTBI. A subset (N=30) underwent a second Aβ-PET scan (mean 2.7 years later). We examined the effect of remote mTBI on Aβ-PET burden, interactions between remote mTBI and age, sex, and APOE status, longitudinal Aβ accumulation, and the interaction between remote mTBI and Aβ burden on memory and executive functioning. RESULTS: Of 134 participants, 48 (36%) reported remote mTBI (0, N=86; 1, N=31, 2+, N=17; mean 37±23 years since last mTBI). Effect size estimates were small to negligible for the association of remote mTBI with Aβ burden (p=.94, η(2)

Background and ObjectivesTraumatic encephalopathy syndrome (TES) has overlapping clinical symptoms with Alzheimer disease (AD). AD pathology commonly co-occurs with chronic traumatic encephalopathy (CTE) pathology. There are currently no validated CTE biomarkers. AD-specific biomarkers such as plasma P-tau181 and P-tau217 may help to identify patients with TES who have AD pathology.MethodsWe measured plasma P-tau181 and P-tau217 (Meso Scale Discovery electrochemiluminescence) in patients with TES, mild cognitive impairment/dementia with biomarker-confirmed AD (“AD”), and healthy controls (“HC”). Patients underwent amyloid-beta (Aβ)-PET and a subset underwent tau-PET using [18F]Flortaucipir. We compared plasma P-tau levels controlling for age and sex and also performed AUC analyses to evaluate the accuracy of group differentiation. In patients with TES, we evaluated associations between plasma P-tau, years of repetitive head impact exposure, and tau-PET. Four TES patients with autopsy-confirmed CTE were described qualitatively.ResultsThe sample included 131 participants (TES, N = 18; AD, N = 65; HC, N = 48). Aβ(+) patients with TES (N = 10), but not Aβ(−) TES, had significantly higher plasma P-tau levels than HC (P-tau181:p< 0.001,d= 1.34; P-tau217:p< 0.001,d= 1.59). There was a trend for Aβ(+) TES having higher plasma P-tau than Aβ(−) TES (P-tau181:p= 0.06,d= 1.06; P-tau217:p= 0.09,d= 0.93). AUC analyses showed good classification of Aβ(+) TES from HC for P-tau181 (AUC = 0.87 [0.71–1.00]) and P-tau217 (AUC = 0.93 [0.86–1.00]). Plasma P-tau217 showed fair differentiation of Aβ(+) TES from Aβ(−) TES (AUC = 0.79 [0.54–1.00],p= 0.04), whereas classification accuracy of P-tau181 was slightly lower and not statistically significant (AUC = 0.71 [0.46–0.96],p= 0.13). Patients with AD had higher tau-PET tracer uptake than Aβ(+) TES and were well differentiated using P-tau181 (AUC = 0.81 [0.68–0.94]) and P-tau217 (AUC = 0.86 [0.73–0.98]). Plasma P-tau correlated with the tau-PET signal in Aβ(+) TES but not in Aβ(−) TES, and there was no association between plasma P-tau and years of repetitive head impact exposure. TES patients with severe CTE and no AD at autopsy had low P-tau181 and P-tau217 levels.DiscussionMeasuring P-tau181 and P-tau217 in plasma may be a feasible and scalable fluid biomarker for identifying AD pathology in TES. Low plasma P-tau levels may be used to increase clinical suspicion of CTE over AD as a primary pathology in TES. Currently, there is no support for P-tau181 or P-tau217 as in vivo biomarkers of CTE tau. Larger studies of patients with pathologically confirmed CTE are needed.Classification of EvidenceThis study provides Class III evidence that (1) among patients with TES and abnormal Aβ-PET scans, elevated plasma P-tau can differentiate between affected individuals and HCs; (2) low plasma P-tau may help identify patients with TES who do not have Alzheimer; and (3) plasma P-tau181 and P-tau217 are not useful biomarkers of patients with TES who do not have AD.

ObjectiveThe clinical phenotype of the rare behavioral variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using PET and postmortem examination.MethodsFor the tau PET study, seven amyloid-P positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardized (W-)scores, by adjusting for age, sex and MMSE in a “typical” memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed bvAD (n=8) and typical AD (n=7) patients.ResultsRegional W-scores ≥1.96 (corresponding to p0.05).ConclusionBoth in-vivo and ex-vivo, bvAD patients showed heterogeneous patterns of tau pathology. Since key regions involved in behavioral regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

IMPORTANCE: Biomarkers for chronic traumatic encephalopathy (CTE) are currently lacking. The radiotracer fluorine F 18–labeled ((18)F)–flortaucipir (FTP) detects tau pathology in Alzheimer disease, and positron emission tomography (PET) with FTP shows elevated binding in individuals at risk for CTE. No study, however, has assessed the correlation between in vivo FTP PET and postmortem tau in CTE. OBJECTIVE: To assess the regional association between in vivo FTP binding and postmortem tau pathology in a patient with pathologically confirmed CTE. DESIGN, SETTING, AND PARTICIPANTS: A white male former National Football League player with 17 years of US football exposure was clinically diagnosed with traumatic encephalopathy syndrome at a neurology tertiary referral center. (18)F-Fludeoxyglucose, carbon 11–labeled Pittsburgh compound B, and FTP PET were performed 52 months prior to death, and magnetic resonance imaging, 50 months prior to death. Brain images were assessed qualitatively for abnormalities blinded to autopsy data. Autopsy was performed using a neurodegenerative research protocol. The FTP standardized uptake value ratios (inferior cerebellar gray reference region) and W-score (age-adjusted z-score) maps were compared with phosphorylated tau immunohistochemical analysis with monoclonal antibody CP13. MAIN OUTCOMES AND MEASURES: Qualitative and quantitative comparisons between antemortem FTP PET and tau pathology at autopsy. RESULTS: Flortaucipir uptake was distributed in a patchy, frontotemporal-predominant pattern that overlapped with regions showing neurodegeneration on magnetic resonance imaging and hypometabolism on (18)F-fludeoxyglucose PET. Pathological assessment revealed stage 4 CTE; limbic argyrophilic grain disease; stage 2 limbic-predominant, age-related transactive response DNA-binding protein 43 encephalopathy; and Braak neurofibrillary tangle stage 3. (18)F-Flortaucipir W-maps matched areas of high postmortem tau burden in left fusiform and inferior temporal gyri and juxtacortical frontal white matter. High FTP W-scores with low tau burden were found in the basal ganglia, thalamus, motor cortex, and calcarine cortex. No regions with low FTP W-scores corresponded to areas with high pathological tau burden. A modest correlation, which did not reach statistical significance (ρ = 0.35, P = .17), was found between FTP standardized uptake value ratio and tau area fraction at the regional level. CONCLUSIONS AND RELEVANCE: In this patient, FTP PET findings during life showed a modest correspondence with postmortem pathology in CTE. These findings suggest that FTP may have limited utility as a tau biomarker in CTE.

We report a group of patients presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions, relatively young age of onset and positive biomarkers for Alzheimer’s pathophysiology. Atypical frontal, dysexecutive/behavioural variants and early-onset variants of Alzheimer’s disease have been previously reported, but no diagnostic criteria exist for a progressive dysexecutive syndrome. In this retrospective review, we report on 55 participants diagnosed with a clinically defined progressive dysexecutive syndrome with 18F-fluorodeoxyglucose-positron emission tomography and Alzheimer’s disease biomarkers available. Sixty-two per cent of participants were female with a mean of 15.2 years of education. The mean age of reported symptom onset was 53.8 years while the mean age at diagnosis was 57.2 years. Participants and informants commonly referred to initial cognitive symptoms as ‘memory problems’ but upon further inquiry described problems with core executive functions of working memory, cognitive flexibility and cognitive inhibitory control. Multi-domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently affected. The frontal and parietal regions which overlap with working memory networks consistently demonstrated hypometabolism on positron emission tomography. Genetic testing for autosomal dominant genes was negative in all eight participants tested and at least one APOE ε4 allele was present in 14/26 participants tested. EEG was abnormal in 14/17 cases with 13 described as diffuse slowing. Furthermore, CSF or neuroimaging biomarkers were consistent with Alzheimer’s disease pathophysiology, although CSF p-tau was normal in 24% of cases. Fifteen of the executive predominate participants enrolled in research neuroimaging protocols and were compared to amnestic (n = 110), visual (n = 18) and language (n = 7) predominate clinical phenotypes of Alzheimer’s disease. This revealed a consistent pattern of hypometabolism in parieto-frontal brain regions supporting executive functions with relative sparing of the medial temporal lobe (versus amnestic phenotype), occipital (versus visual phenotype) and left temporal (versus language phenotype). We propose that this progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype disambiguated from behavioural presentations and not linked specifically to the frontal lobe or a particular anatomic substrate without further study. This clinical presentation can be due to Alzheimer’s disease but is likely not specific for any single aetiology. Diagnostic criteria are proposed to facilitate additional research into this understudied clinical presentation., We present a retrospective case series of 55 individuals presenting with a progressive dysexecutive syndrome with biomarker evidence of Alzheimer’s disease. This clinical syndrome should be recognized as a distinct clinical phenotype that is disambiguated form behavioural presentations and not linked to a particular anatomic substrate without further study., Graphical Abstract Graphical Abstract

Spinal cord infarctions (SCIs) predominantly affect the anterior spinal artery (ASA) territory and manifest with acute weakness and loss of pain and temperature sensation. In comparison, posterior spinal artery (PSA) infarctions are more rare,1 possibly due to paired PSAs with increased collateral arterial supply; the diagnosis may also be underrecognized.1–5 Reports on clinical and radiologic features and outcomes of PSA infarcts are scant. We sought to describe all PSA infarcts seen at Mayo Clinic (1997–2017) to improve the understanding and awareness of this uncommon myelopathy. All patients consented to use of their medical records for research.

Historically, payment for cognitive, nonprocedural care has required provision of face-to-face evaluation and management as part of general ambulatory or inpatient care. Although non-face-to-face patient care (e.g., care via electronic means or telephone) is commonly performed and is integral to patient-centered care, appropriate reimbursement for this type of care is lacking. Beginning in 2017, Centers for Medicare and Medicaid (CMS) has taken a large step forward in reimbursing an increased number of cognitive care and non-face-to-face codes. CMS has also included language indicating that nonphysician providers (i.e., nurse practitioners and physician assistants) can perform many of these services independently. The 2017 and now the 2018 fee schedules thus create new payments for non-face-to-face, patient-centered services, and may allow neurologists to reach out to more patients through nonphysician providers. As health care in the United States moves toward value-based incentives, these newly supported non-face-to-face services will provide neurologists with new tools to deliver sustainable, high-value care.

A 75-year-old woman with a history of multiple resolved hemiparetic strokes presented with unilateral ischemic stroke causing sudden loss of volitional control of the musculature crucial for speaking and swallowing. Automatic movements, such as laughter and yawning, were preserved (video 1 and figure). She was diagnosed with Foix-Chavany-Marie syndrome (FCMS). Lesions of the operculum or its projections to brainstem nuclei can cause FCMS.1 Because these muscles receive bilateral innervation, a new unilateral lesion can produce sudden bilateral weakness if an old contralateral lesion was compensated by the intact hemisphere. Spontaneous movements, controlled by extrapyramidal pathways, are preserved.2

See Gordon (doi:10.1093/brain/awy052) for a scientific commentary on this article.Predicting underlying pathology based on clinical presentation has historically proven difficult, especially in older cohorts. Age-related hippocampal sclerosis may account for a significant proportion of elderly participants with amnestic dementia. Advances in molecular neuroimaging have allowed for detailed biomarker-based phenotyping, but in the absence of antemortem markers of hippocampal sclerosis, cases of mixed pathology remain problematic. We evaluated the utility of 18F-FDG-PET to differentiate flortaucipir tau PET negative from flortaucipir positive amnestic mild cognitive impairment and dementia and used an autopsy confirmed cohort to test the hypothesis that hippocampal sclerosis might account for the observed pattern. We identified impaired participants (Clinical Dementia Rating > 0) with amnestic presentations ≥ 75 years who had MRI and PET imaging with 18F-FDG (glucose metabolism), Pittsburgh compound B (amyloid) and flortaucipir (tau) performed within a year of cognitive assessment. These were stratified into amyloid positive/negative and tau positive/negative according to the A/T/N classification scheme. Our sample included 15 amyloid and tau-positive participants, and nine tau-negative participants (five of whom were amyloid-positive). For the autopsy cohort, sequential cases with antemortem 18F-FDG-PET were screened and those with TDP-43-negative Alzheimer's disease (10 cases) and TDP-43-positive hippocampal sclerosis (eight cases) were included. We compared each group to controls and to each other in a voxel-based analysis, and supplemented this with a region of interest-based analysis comparing medial to inferior temporal metabolism. Tau-positive and negative cases did not differ on neuropsychological testing or structural magnetic resonance biomarkers. Tau-negative cases had focal medial temporal and posterior cingulate/retrosplenial hypometabolism regardless of amyloid status, whereas tau-positive cases had additional lateral parietal and inferior temporal involvement. The inferior/medial temporal metabolism ratio was significantly different between the groups with the tau-negative group having a higher ratio. In the autopsy series, hippocampal sclerosis cases had greater medial temporal hypometabolism than Alzheimer's disease cases, who had more parietal and lateral/inferior temporal hypometabolism. Again, the ratio between temporal regions of interest differed significantly between groups. Two of the tau-negative patients, both of whom had an elevated inferior/medial temporal ratio, came to autopsy during the study and were found to have hippocampal sclerosis. Our finding that tau-negative amnestic mild cognitive impairment and dementia is associated with focal medial temporal and posterior cingulate hypometabolism extends prior reports in amyloid-negative cases. The inferior/medial temporal metabolism ratio can help identify tau-negative cases of amnestic dementia and may serve as a biomarker for hippocampal sclerosis.

ObjectiveTo describe the phenomenon of tau-negative amnestic dementia mimicking Alzheimer disease (AD) clinically and radiologically and to highlight the importance of biomarkers in AD research.MethodsEight participants with amnestic mild cognitive impairment or AD dementia were evaluated by a behavioral neurologist and had a standardized neuropsychological battery performed. All participants completed structural (MRI) and molecular (amyloid and tau PET) imaging. AD-signature thickness and adjusted hippocampal volume served as structural biomarkers, while standardized uptake value ratios (SUVRs) from validated regions of interest for amyloid and tau PET were used to determine molecular biomarker status.ResultsAll participants were thought to have AD as the primary driver of their symptoms before any PET imaging. All participants had hippocampal atrophy, and 2 participants fell below the AD-signature thickness cutoff for elderly controls (2.57), with a further 3 falling below the more stringent cutoff based on young controls (2.67). Four participants were amyloid positive (SUVR >1.42), and all were tau negative (SUVR ConclusionsThe participants presented here were clinically impaired, with structural imaging evidence of neurodegeneration, in the absence of any significant tau accumulation. Therefore, AD is unlikely as a cause of their clinical presentation and neurodegenerative imaging findings. Several implications are discussed, including the need to establish amyloid and tau positivity in N+ participants before enrolling them in trials of disease-modifying therapy agents for AD.

Importance Erythromelalgia is a clinical diagnosis based on intermittent warmth, erythema, and pain in the distal extremities. One problem facing physicians is how to objectively test for this disease. Given that other painful conditions of the distal extremities (ie, neuropathy related to human immunodeficiency virus, diabetes, or Fabry disease) can be evaluated with a skin biopsy to visualize pathologically decreased densities of the small nerve fibers that innervate the epidermis, one hypothesis is that erythromelalgia could similarly be associated with a loss of epidermal nerve fiber density (ENFD). Objectives To examine whether erythromelalgia is associated with a structural loss of small fibers using the ENFD technique and to compare this with functional studies of small nerve fibers. Design, Setting, and Participants In a retrospective study of 52 consecutive patients with erythromelalgia who were seen between September 1, 2010, and September 22, 2015, patients were interviewed and examined and their conditions clinically diagnosed by a board-certified dermatologist at a large tertiary referral center, where ENFD testing became a routine part of evaluating erythromelalgia in 2010. Thus, all 52 consecutive patients were included solely based on their clinical diagnosis of erythromelalgia. For quantification of ENFD, observers were masked to all patient information except for name and clinic number. Main Outcomes and Measures The hypothesis that patients with erythromelalgia would have decreased ENFD was formulated before data collection. Epidermal nerve fiber density, the primary outcome, is a measurement of the density of small nerve fibers within the epidermis. Secondary measures included functional small fiber evaluation, such as autonomic (heart rate, blood pressure, and sweat testing) and subjective testing of pain. Results In this cohort study, 52 consecutively seen patients were identified (female, 42 [80%]; median age, 44 years; age range, 13-82 years). Whereas only 5 of 52 patients (10%) had ENFD at or below the fifth percentile of healthy control individuals, most patients had functional abnormalities of these small fibers; 29 patients (60%) had abnormal sweat test results, 21 (42%) had abnormal pain thresholds, and 20 (38%) had abnormal blood pressure or heart rate control. Conclusions and Relevance Unlike other diseases of the small nerve fibers that cause acral pain syndromes, erythromelalgia is not characterized by loss of ENFD. However, most patients have impaired function of these small fibers. Physicians would benefit from performing functional rather than structural small fiber studies when evaluating erythromelalgia.

Current therapies for treating skeletal pain have significant limitations as available drugs (non-steroidal anti-inflammatory drugs and opiates) have significant unwanted side effects. Targeting nerve growth factor (NGF) or its cognate receptor tropomysin receptor kinase A (TrkA) has recently become an attractive target for inhibition of adult skeletal pain. Here we explore whether sustained administration of a selective small molecule Trk inhibitor that blocks TrkA, TrkB and TrkC kinase activity with nanomolar affinity reduces skeletal pain while allowing the maintenance of sensory and sympathetic neurons in the adult mouse. Twice-daily administration of a Trk inhibitor was begun 1 day post fracture and within 8 h of acute administration fracture pain-related behaviors were reduced by 50% without significant sedation, weight gain or inhibition of fracture healing. Following administration of the Trk inhibitor for 7 weeks, there was no significant decline in the density of unmyelinated or myelinated sensory nerve fibers, sympathetic nerve fibers, measures of acute thermal pain, acute mechanical pain, or general neuromuscular function. The present results suggest that sustained administration of a peripherally selective TrkA, B and C inhibitor significantly reduces skeletal pain without having any obvious detrimental effects on adult sensory and sympathetic nerve fibers or early fracture healing. As with any potential therapeutic advance, understanding whether the benefits of Trk blockade are associated with any risks or unexpected effects will be required to fully appreciate the patient populations that may benefit from this therapeutic approach.

For many patients, pain is the first sign of cancer and, while pain can be present at any time, the frequency and intensity of pain tend to increase with advancing stages of the disease. Thus, between 75 and 90% of patients with metastatic or advanced-stage cancer will experience significant cancer-induced pain. One major unanswered question is why cancer pain increases and frequently becomes more difficult to fully control with disease progression. To gain insight into this question we used a mouse model of bone cancer pain to demonstrate that as tumor growth progresses within bone, tropomyosin receptor kinase A (TrkA)-expressing sensory and sympathetic nerve fibers undergo profuse sprouting and form neuroma-like structures. To address what is driving the pathological nerve reorganization we administered an antibody to nerve growth factor (anti-NGF). Early sustained administration of anti-NGF, whose cognate receptor is TrkA, blocks the pathological sprouting of sensory and sympathetic nerve fibers, the formation of neuroma-like structures, and inhibits the development of cancer pain. These results suggest that cancer cells and their associated stromal cells release nerve growth factor (NGF), which induces a pathological remodeling of sensory and sympathetic nerve fibers. This pathological remodeling of the peripheral nervous system then participates in driving cancer pain. Similar to therapies that target the cancer itself, the data presented here suggest that, the earlier therapies blocking this pathological nerve remodeling are initiated, the more effective the control of cancer pain.

Pain frequently accompanies cancer. What remains unclear is why this pain frequently becomes more severe and difficult to control with disease progression. Here we test the hypothesis that with disease progression, sensory nerve fibers that innervate the tumor-bearing tissue undergo a pathological sprouting and reorganization, which in other nonmalignant pathologies has been shown to generate and maintain chronic pain. Injection of canine prostate cancer cells into mouse bone induces a remarkable sprouting of calcitonin gene-related peptide (CGRP+) and neurofilament 200 kDa (NF200+) sensory nerve fibers. Nearly all sensory nerve fibers that undergo sprouting also coexpress tropomyosin receptor kinase A (TrkA+). This ectopic sprouting occurs in sensory nerve fibers that are in close proximity to colonies of prostate cancer cells, tumor-associated stromal cells and newly formed woven bone, which together form sclerotic lesions that closely mirror the osteoblastic bone lesions induced by metastatic prostate tumors in humans. Preventive treatment with an antibody that sequesters nerve growth factor (NGF), administered when the pain and bone remodeling were first observed, blocks this ectopic sprouting and attenuates cancer pain. Interestingly, reverse transcription PCR analysis indicated that the prostate cancer cells themselves do not express detectable levels of mRNA coding for NGF. This suggests that the tumor-associated stromal cells express and release NGF, which drives the pathological reorganization of nearby TrkA+sensory nerve fibers. Therapies that prevent this reorganization of sensory nerve fibers may provide insight into the evolving mechanisms that drive cancer pain and lead to more effective control of this chronic pain state.

In the United States, cancer is the second most common cause of death and it is expected that about 562,340 Americans will have died of cancer in 2009. Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone. Once tumors metastasize to bone, they are a major cause of morbidity and mortality as the tumor induces significant skeletal remodeling, fractures, pain, and anemia. Currently, the factors that drive cancer pain are poorly understood. However, several recently introduced models of bone cancer pain, which closely mirror the human condition, are providing insight into the mechanisms that drive bone cancer pain and guide the development of mechanism-based therapies to treat the cancer pain. Several of these mechanism-based therapies have now entered human clinical trials. If successful, these therapies have the potential to significantly enlarge the repertoire of modalities that can be used to treat bone cancer pain and improve the quality of life, functional status, and survival of patients with bone cancer.

Although musculoskeletal pain is one of the most common causes of chronic pain and physical disability in both developing and developed countries, relatively little is known about the nerve fibers and mechanisms that drive skeletal pain. Small diameter sensory nerve fibers, most of which are C-fiber nociceptors, can be separated into two broad populations: the peptide-rich and peptide-poor nerve fibers. Peptide-rich nerve fibers express substance P (SP) and calcitonin gene-related peptide (CGRP). In contrast, the peptide-poor nerve fibers bind to isolectin B4 (IB(4)) and express the purinergic receptor P(2)X(3) and Mas-related G protein-coupled receptor member d (Mrgprd). In the present report, we used mice in which the Mrgprd(+) nerve fibers express genetically encoded axonal tracers to determine the peptide-rich and peptide-poor sensory nerve fibers that innervate the glabrous skin of the hindpaw as compared to the bone marrow, mineralized bone and periosteum of the femur. Whereas the skin is richly innervated by CGRP(+), SP(+), P(2)X(3)(+) and Mrgprd(+) sensory nerve fibers, the bone marrow, mineralized bone and periosteum receive a significant innervation by SP(+) and CGRP(+), but not Mrgprd(+) and P(2)X(3)(+) nerve fibers. This lack of redundancy in the populations of C-fibers that innervate the bone may present a unique therapeutic opportunity for targeting skeletal pain as the peptide-rich and peptide-poor sensory nerve fibers generally express a different repertoire of receptors and channels to detect noxious stimuli. Thus, therapies that target the specific types of C-nerve fibers that innervate the bone may be uniquely effective in attenuating skeletal pain as compared to skin pain.

Pain often accompanies cancer and most current therapies for treating cancer pain have significant unwanted side effects. Targeting nerve growth factor (NGF) or its cognate receptor tropomyosin receptor kinase A (TrkA) has become an attractive target for attenuating chronic pain. In the present report, we use a mouse model of bone cancer pain and examine whether oral administration of a selective small molecule Trk inhibitor (ARRY-470, which blocks TrkA, TrkB and TrkC kinase activity at low nm concentrations) has a significant effect on cancer-induced pain behaviors, tumor-induced remodeling of sensory nerve fibers, tumor growth and tumor-induced bone remodeling. Early/sustained (initiated day 6 post cancer cell injection), but not late/acute (initiated day 18 post cancer cell injection) administration of ARRY-470 markedly attenuated bone cancer pain and significantly blocked the ectopic sprouting of sensory nerve fibers and the formation of neuroma-like structures in the tumor bearing bone, but did not have a significant effect on tumor growth or bone remodeling. These data suggest that, like therapies that target the cancer itself, the earlier that the blockade of TrkA occurs, the more effective the control of cancer pain and the tumor-induced remodeling of sensory nerve fibers. Developing targeted therapies that relieve cancer pain without the side effects of current analgesics has the potential to significantly improve the quality of life and functional status of cancer patients.

Although skeletal pain can have a marked impact on a patient's functional status and quality of life, relatively little is known about the specific populations of peripheral nerve fibers that drive non-malignant bone pain. In the present report, neonatal male Sprague-Dawley rats were treated with capsaicin or vehicle and femoral fracture was produced when the animals were young adults (15-16 weeks old). Capsaicin treatment, but not vehicle, resulted in a significant (>70%) depletion in the density of calcitonin-gene related peptide positive (CGRP(+)) sensory nerve fibers, but not 200 kDa neurofilament H positive (NF200(+)) sensory nerve fibers in the periosteum. The periosteum is a thin, cellular and fibrous tissue that tightly adheres to the outer surface of all but the articulated surface of bone and appears to play a pivotal role in driving fracture pain. In animals treated with capsaicin, but not vehicle, there was a 50% reduction in the severity, but no change in the time course, of fracture-induced skeletal pain-related behaviors as measured by spontaneous flinching, guarding and weight bearing. These results suggest that both capsaicin-sensitive (primarily CGRP(+) C-fibers) and capsaicin-insensitive (primarily NF200(+) A-delta fibers) sensory nerve fibers participate in driving skeletal fracture pain. Skeletal pain can be a significant impediment to functional recovery following trauma-induced fracture, osteoporosis-induced fracture and orthopedic surgery procedures such as knee and hip replacement. Understanding the specific populations of sensory nerve fibers that need to be targeted to inhibit the generation and maintenance of skeletal pain may allow the development of more specific mechanism-based therapies that can effectively attenuate acute and chronic skeletal pain.

Narcolepsy and idiopathic hypersomnia are commonly treated by sleep specialists and encountered by other medical providers. Although pharmacotherapy with modafinil and traditional stimulants is considered the mainstay of treatment, physicians are often uncomfortable with their prescription because of concerns regarding misuse. The goal of this study was to assess the frequency of stimulant misuse in this population.A retrospective cohort study was performed evaluating patients 18 years and older diagnosed with narcolepsy with and without cataplexy and idiopathic hypersomnia with and without long sleep between 2003-2008. Patients were included if they obtained stimulant prescriptions from and had at least one follow-up visit subsequent to initial diagnosis at our center. Stimulant misuse was defined by multiple prescription sources or early refill requests, which are systematically entered into the record by nursing staff.A total of 105 patients met inclusion criteria for the study; 45 (42%) were male. Mean age at multiple sleep latency test was 42 (± 16). Twelve (11%) patients had a history of illicit substance misuse, and one (1%) patient demonstrated previous stimulant misuse. Fifty-seven (54%) patients carried psychiatric diagnoses, 88% of whom reported depression. Median duration of monitored stimulant therapy was 26 months (range 1-250). None of the 105 patients was found to have evidence of stimulant misuse.This study suggests that the frequency of stimulant misuse in patients with narcolepsy and idiopathic hypersomnia is extremely low. Concerns regarding drug misuse should not leverage decisions to provide long-term therapy.

Although skeletal pain is a leading cause of chronic pain and disability, relatively little is known about the specific populations of nerve fibers that innervate the skeleton. Recent studies have reported that therapies blocking nerve growth factor (NGF) or its cognate receptor, tropomyosin receptor kinase A (TrkA) are efficacious in attenuating skeletal pain. A potential factor to consider when assessing the analgesic efficacy of targeting NGF-TrkA signaling in a pain state is the fraction of NGF-responsive TrkA+ nociceptors that innervate the tissue from which the pain is arising, as this innervation and the analgesic efficacy of targeting NGF-TrkA signaling may vary considerably from tissue to tissue. To explore this in the skeleton, tissue slices and whole mount preparations of the normal, adult mouse femur were analyzed using immunohistochemistry and confocal microscopy. Analysis of these preparations revealed that 80% of the unmyelinated/thinly myelinated sensory nerve fibers that express calcitonin gene-related peptide (CGRP) and innervate the periosteum, mineralized bone and bone marrow also express TrkA. Similarly, the majority of myelinated sensory nerve fibers that express neurofilament 200 kDa (NF200) which innervate the periosteum, mineralized bone and bone marrow also co-express TrkA. In the normal femur, the relative density of CGRP+, NF200+ and TrkA+ sensory nerve fibers per unit volume is: periosteum > bone marrow > mineralized bone > cartilage with the respective relative densities being 100: 2: 0.1: 0. The observation that the majority of sensory nerve fibers innervating the skeleton express TrkA+, may in part explain why therapies that block NGF/TrkA pathway are highly efficacious in attenuating skeletal pain.

In the United States, cancer is the second most common cause of death and it is expected that about 562,340 Americans will have died of cancer in 2009. Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone. Once tumors metastasize to bone, they are a major cause of morbidity and mortality as the tumor induces significant skeletal remodeling, fractures, pain, and anemia. Currently, the factors that drive cancer pain are poorly understood. However, several recently introduced models of bone cancer pain, which closely mirror the human condition, are providing insight into the mechanisms that drive bone cancer pain and guide the development of mechanism-based therapies to treat the cancer pain. Several of these mechanism-based therapies have now entered human clinical trials. If successful, these therapies have the potential to significantly enlarge the repertoire of modalities that can be used to treat bone cancer pain and improve the quality of life, functional status, and survival of patients with bone cancer.

This study attempts to quantify the impact of the introduction of local second-level health services on nonmedical costs (NMCs) for residents of the rural Ecuadorian county of La Maná.NMCs for patients accessing second-level health care were assessed by using a quasi-experimental pre- and postintervention study design. In 2007, before local second-level health care services existed, and then in 2008, after the introduction of second-level health care services in the form of a county hospital, 508 patients from the county who sought second-level health care were interviewed.Mean NMCs per patient per illness episode were US$ 93.58 before the county hospital opened and US$ 12.62 after it opened. This difference was largely due to reductions in transport costs (US$ 50.01 vs. US$ 4.28) and food costs (US$ 25.38 vs. US$ 7.28) (P0.001 for each category).NMCs can be decreased sevenfold with the introduction of a county hospital in a rural province previously lacking second-level health care. Introduction of rural second-level health care reduces financial barriers and thus may increase access to these health services for poorer patients in rural communities.

As humans age there is a decline in most sensory systems including vision, hearing, taste, smell, and tactile acuity. In contrast, the frequency and severity of musculoskeletal pain generally increases with age. To determine whether the density of sensory nerve fibers that transduce skeletal pain changes with age, calcitonin gene related peptide (CGRP) and neurofilament 200 kDa (NF200) sensory nerve fibers that innervate the femur were examined in the femurs of young (4-month-old), middle-aged (13-month-old) and old (36-month-old) male F344/BNF1 rats. Whereas the bone quality showed a significant age-related decline, the density of CGRP(+) and NF200(+) nerve fibers that innervate the bone remained remarkably unchanged as did the severity of acute skeletal fracture pain. Thus, while bone mass, quality, and strength undergo a significant decline with age, the density of sensory nerve fibers that transduce noxious stimuli remain largely intact. These data may in part explain why musculoskeletal pain increases with age.

Erratum to “A phenotypically restricted set of primary afferent nerve fibers innervate the bone versus skin: Therapeutic opportunity for treating skeletal pain” [Bone 46 (2010) 306–313] Juan Miguel Jimenez-Andrade , William G. Mantyh , Aaron P. Bloom , Haili Xu , Alice S. Ferng , Gregory Dussor , Todd W. Vanderah , Patrick W. Mantyh a,c,d,⁎ a Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA b Physiological Sciences, College of Medicine, University of Arizona, Tucson, AZ 85724, USA c Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA d Research Service, VA Medical Center, Minneapolis, MN 55417, USA