Authors 

William G. Mantyh, MD; Adam D. Block, BS; Madelyn R. Castro, BS; Adam Hansen, BS; Matti J. Matheson, APRN; Corey Strong Jr, BS; Annamarie Hill, MA; Zuzan Cayci, MD; J. Neil Henderson, PhD

Abstract

Importance: Visual hallucinations are a core feature of dementia with Lewy bodies and primary psychiatric disease, yet identification of a hallucination vs normal spiritual experience depends on cultural context. Almost no information exists in the medical literature regarding normal spiritual experiences in American Indian participants in the context of a neurocognitive evaluation. 

Objective: To assess the characteristics of a normal spiritual experience in an Ojibwe Tribal Nation. Design, Setting, and Participants: This prospective, cross-sectional study was conducted between August 1, 2021, and August 31, 2022, among an Ojibwe Tribal Nation in northern Minnesota. Participants were evaluated at their tribal nation clinic. Cognitively unimpaired tribal Elders who were enrolled members of the tribal nation and aged 55 years or older were invited to participate via fliers, radio advertisements, and health fair presentations. Thirty-seven tribal Elders volunteered. 

Main Outcomes and Measures: Each participant was asked whether they experienced hallucinations or visions of people, animals, or objects that are not part of the physical world. This was an a priori formulated question and part of a comprehensive neurocognitive evaluation consisting of history and physical examination (including cognitive screening with a subspecialty-trained behavioral neurologist); blood tests for metabolic, nutritional, and thyroid conditions; and noncontrast magnetic resonance imaging brain scan. Four patients were excluded from the present analysis due to having mild cognitive impairment or dementia. 

Results: Thirty-three cognitively unimpaired tribal Elders (mean [SD] age, 66.0 [7.5] years; 22 women [67%]) were included. Sixteen (48%) answered affirmatively, reporting recurrent visions of the nonphysical world. Generally, these visions were well formed, benevolent in nature, and transient; started in preadolescence; involved spirits or ancestors; and were congruent with cultural and spiritual beliefs of the Ojibwe people. No patients had accompanying dream enactment behavior, dysautonomia, parkinsonism, sleep transition-related hallucinations, or moderate to severe depression to suggest a prodrome of an α-synucleinopathy, hypnopompic or hypnagogic hallucinations, or psychosis. 

Conclusions and Relevance: Although based on only 1 Ojibwe Tribal Nation, this study suggests that formed visions of the nonphysical world are common among cognitively healthy Ojibwe individuals and can represent normal spiritual experiences. Clinicians would benefit from careful consideration of cultural or spiritual context to avoid misdiagnosis of neuropsychiatric disease.

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Authors

Breton M. Asken, Jeremy A. Tanner, Leslie S. Gaynor, Lawren VandeVrede , William G. Mantyh, Kaitlin B. Casaletto, Adam M. Stafaroni, Corrina Fonseca, Ranjani Shankar, Harli Grant, Karen Smith, Argentina Lario Lago, Haiyan Xu, Renaud La Joie, Yann Cobigo, Howie Rosen, David C. Perry, Julio C. Rojas, Bruce L. Miller, Raquel C. Gardner, Kevin K. W. Wang, Joel H. Kramer and Gil D. Rabinovici

Abstract

Background: Traumatic encephalopathy syndrome (TES) is a clinical phenotype sensitive but non-specific to underlying chronic traumatic encephalopathy (CTE) neuropathology. However, cognitive symptoms of TES overlap with Alzheimer’s disease (AD), and features of AD pathology like beta-amyloid (Aβ) plaques often co-occur with CTE, making clinical-to-pathological conclusions of TES diagnoses challenging. We investigated how Alzheimer’s neuropathological changes associated with cognition, brain volume, and plasma biomarkers in patients with repetitive head impacts (RHI)/TES, clinical AD, or typically aging controls. 

Methods: We studied 154 participants including 33 with RHI/TES (age 61.5 ± 11.5, 100% male, 11/33 Aβ[+]), 62 with AD and no known prior RHI (age 67.1 ± 10.2, 48% male, 62/62 Aβ[+]), and 59 healthy controls without RHI (HC; age 73.0 ± 6.2, 40% male, 0/59 Aβ[+]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (voxel-based morphometry analysis), and provided plasma samples analyzed for GFAP, NfL, IL-6, IFN-γ, and YKL-40. For cognition and plasma biomarkers, patients with RHI/TES were stratified as Aβ[+] or Aβ[−] and compared to each other plus the AD and HC groups (ANCOVA adjusting for age and sex). Differences with at least a medium effect size (Cohen’s d > 0.50) were interpreted as potentially meaningful. 

Results: Cognitively, within the TES group, Aβ[+] RHI/TES performed worse than Aβ[-] RHI/TES on visuospatial (p =.04, d = 0.86) and memory testing (p =.07, d = 0.74). Comparing voxel-wise brain volume, both Aβ[+] and Aβ[−] RHI/TES had lower medial and anterior temporal lobe volume than HC and did not significantly differ from AD. Comparing plasma biomarkers, Aβ[+] RHI/TES had higher plasma GFAP than HC (p =.01, d = 0.88) and did not significantly differ from AD. Conversely, Aβ[−] RHI/TES had higher NfL than HC (p =.004, d = 0.93) and higher IL-6 than all other groups (p’s ≤.004, d’s > 1.0). Conclusions: Presence of Alzheimer’s pathology in patients with RHI/TES is associated with altered cognitive and biomarker profiles. Patients with RHI/TES and positive Aβ-PET have cognitive and plasma biomarker changes that are more like patients with AD than patients with Aβ[−] RHI/TES. Measuring well-validated Alzheimer’s biomarkers in patients with RHI/TES could improve interpretation of research findings and heighten precision in clinical management.

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Authors

William G. Mantyh, J. Nicholas Cochran,  Jared W. Taylor, Iris J. Broce, Ethan G. Geier,  Luke W. Bonham, Ashlyn G. Anderson, Daniel W. Sirkis, Renaud La Joie, Leonardo Iaccarino, Kiran Chaudhary, Lauren Edwards, Amelia Strom, Harli Grant, Isabel E. Allen, Zachary A. Miller, Marilu L. Gorno‐Tempini, Joel H. Kramer, Bruce L. Miller, Rahul S. Desikan, † Gil D. Rabinovici, and Jennifer S. Yokoyama 

Early-onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early-onset AD patients without an identified autosomal dominant cause, we hypothesized that their early-onset disease reflects further enrichment of the common risk-conferring single nucleotide polymorphisms associated with late-onset AD. We applied a previously validated polygenic hazard score for late-onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early-onset AD. For comparison, we included 179 participants with late-onset AD and 70 healthy controls. Polygenic hazard scores were similar in early- versus late-onset AD. The polygenic hazard score was not associated with age-of-onset or disease biomarkers within early-onset AD. Early-onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late-onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted.Highlights: There is a unique genetic architecture of early- versus late-onset Alzheimer's disease (AD).Late-onset AD polygenic risk is not an explanation for early-onset AD.Polygenic risk of late-onset AD does not predict early-onset AD biology.Unique genetic architecture of early- versus late-onset AD parallels AD heterogeneity.

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Authors

Yongkang Xiao, Yu Hou, Huixue Zhou, Gayo Diallo, Marcelo Fiszman, Julian Wolfson, Halil Kilicoglu, You Chen, Chang Su, Hua Xu, William G Mantyh, Rui Zhang

Abstract

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.

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Authors

Breton M. Asken, PhD, ATC, Jeremy A. Tanner, MD, Lawren VandeVrede, MD, PhD, William G. Mantyh, MD, Kaitlin B. Casaletto, PhD, Adam M. Staffaroni, PhD, Renaud La Joie, PhD, Leonardo Iaccarino, PhD, David Soleimani-Meigooni, MD, Julio C. Rojas, MD, PhD, Raquel C. Gardner, MD, Bruce L. Miller, MD, Lea T. Grinberg, MD, PhD, Adam L. Boxer, MD, PhD, Joel H. Kramer, PsyD, and Gil D. Rabinovici, MD

Abstract

Background and Objectives: Traumatic 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.

Methods: We 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.

Results: The 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.

Discussion: Measuring 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.

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Authors

Alice S Tang, Tomiko Oskotsky, Shreyas Havaldar, William G Mantyh, Mesude Bicak, Caroline Warly Solsberg, Sarah Woldemariam, Billy Zeng, Zicheng Hu, Boris Oskotsky, Dena Dubal, Isabel E Allen, Benjamin S Glicksberg, Marina Sirota

Abstract

Alzheimer’s Disease (AD) is a neurodegenerative disorder that is still not fully understood. Sex modifies AD vulnerability, but the reasons for this are largely unknown. We utilize two independent electronic medical record (EMR) systems across 44,288 patients to perform deep clinical phenotyping and network analysis to gain insight into clinical characteristics and sex-specific clinical associations in AD. Embeddings and network representation of patient diagnoses demonstrate greater comorbidity interactions in AD in comparison to matched controls. Enrichment analysis identifies multiple known and new diagnostic, medication, and lab result associations across the whole cohort and in a sex-stratified analysis. With this data-driven method of phenotyping, we can represent AD complexity and generate hypotheses of clinical factors that can be followed-up for further diagnostic and predictive analyses, mechanistic understanding, or drug repurposing and therapeutic approaches.

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Authors

Breton M Asken, William G Mantyh, Renaud La Joie, Amelia Strom, Kaitlin B Casaletto, Adam M Staffaroni, Alexandra C Apple, Cutter A Lindbergh, Leonardo Iaccarino, Michelle You, Harli Grant, Corrina Fonseca, Charles Windon, Kyan Younes, Jeremy Tanner, Gil D Rabinovici, Joel H Kramer, Raquel C Gardner

Abstract

We investigated whether clinically normal older adults with remote, mild traumatic brain injury (mTBI) show evidence of higher cortical Aβ burden. Our study included 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. 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, η2 < 0.01), and for all interaction analyses. Longitudinally, we found a non-statistically significant association of those with remote mTBI (N = 11) having a faster rate of Aβ accumulation (B = 0.01, p =.08) than those without (N = 19). There was no significant interaction between remote mTBI and Aβ burden on cognition. In clinically normal older adults, history of mTBI is not associated with greater cortical Aβ burden and does not interact with Aβ burden to impact cognition. Longitudinal analyses suggest remote mTBI may be associated with more rapid cortical Aβ accumulation. This finding warrants further study in larger and more diverse samples with well-characterized lifelong head trauma exposure.

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Authors

Ellen Singleton, Oskar Hansson, Yolande A L Pijnenburg, Renaud La Joie, William G Mantyh, Pontus Tideman, Erik Stomrud, Antoine Leuzy, Maurits Johansson, Olof Strandberg, Ruben Smith, Evi Berendrecht, Bruce L Miller, Leonardo Iaccarino, Lauren Edwards, Amelia Strom, Emma E Wolters, Emma Coomans, Denise Visser, Sandeep S V Golla, Hayel Tuncel, Femke Bouwman, John Cornelis Van Swieten, Janne M Papma, Bart van Berckel, Philip Scheltens, Anke A Dijkstra, Gil D Rabinovici, Rik Ossenkoppele 

Abstract

Objective: The 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. 

Methods: For the tau PET study, seven amyloid-β positive bvAD patients underwent [ 18 F]flortaucipir or [ 18 F]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). 

Results: Individual regional W-scores ≥1.96 (corresponding to p<0.05) were observed in three cases, that is, case #5: medial prefrontal cortex (W=2.13) and anterior default mode network (W=3.79), case #2: lateral prefrontal cortex (W=2.79) and salience network (W=2.77), and case #7: frontal-to-entorhinal ratio (W=2.04). The remaining four cases fell within the normal distributions of the tAD group. Postmortem AT8 staining indicated no group-level regional differences in phosphorylated tau levels between bvAD and tAD (all p>0.05). Conclusions Both 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.

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Authors

William G Mantyh, Salvatore Spina, Alex Lee, Leonardo Iaccarino, David Soleimani-Meigooni, Elena Tsoy, Taylor J Mellinger, Harli Grant, Lawren Vandevrede, Renaud La Joie 1, Orit Lesman-Segev, Stephanie Gaus, Katherine L Possin, Lea T Grinberg, Bruce L Miller, William W Seeley, Gil D Rabinovici 

Abstract

Importance: Biomarkers for chronic traumatic encephalopathy (CTE) are currently lacking. The radiotracer fluorine F 18-labeled (18F)-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. 18F-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 18F-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. 18F-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.

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Authors

Ryan A Townley, Jonathan Graff-Radford, William G Mantyh, Hugo Botha, Angelina J Polsinelli, Scott A Przybelski, Mary M Machulda, Ahmed T Makhlouf, Matthew L Senjem, Melissa E Murray, Ross R Reichard, Rodolfo Savica, Bradley F Boeve, Daniel A Drubach, Keith A Josephs, David S Knopman, Val J Lowe, Clifford R Jack Jr, Ronald C Petersen, David T Jones 

Abstract

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.

Authors

William G. Mantyh, MD, Adithya Chandregowda, PhD, Jimmy R. Fulgham, MD, Kelly D. Flemming, MD, Ruple S. Laughlin, MD, and David T. Jones,

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

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Authors

Hugo Botha, William G Mantyh, Melissa E Murray, David S Knopman, Scott A Przybelski, Heather J Wiste, Jonathan Graff-Radford, Keith A Josephs, Christopher G Schwarz, Walter K Kremers, Bradley F Boeve, Ronald C Petersen, Mary M Machulda, Joseph E Parisi, Dennis W Dickson, Val Lowe, Clifford R Jack Jr, David T Jones

Abstract

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.

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Authors

Nicholas L. Zalewski, MD, Alejandro A. Rabinstein, MD, Eelco F.M. Wijdicks, MD, George W. Petty, MD, Sean J. Pittock, MD, William G. Mantyh, MD, and Eoin P. Flanagan, MBBCh

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Authors

William G. Mantyh, MD, Bruce H. Cohen, MD, Luana Ciccarelli, CPC, CRC, Lindsey M. Philpot, PhD,, and Lyell K. Jones, Jr, MD

Abstract

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.

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Authors

Hugo Botha, MBChB, William G. Mantyh, MD, Jonathan Graff-Radford, MD, Mary M. Machulda, PhD, Scott A. Przybelski, Heather J. Wiste, Matthew L. Senjem, MS, Joseph E. Parisi, MD, Ronald C. Petersen, MD, PhD, Melissa E. Murray, PhD, Bradley F. Boeve, MD, Val J. Lowe, MD, David S. Knopman, MD, Clifford R. Jack, Jr, MD, and David T. Jones, MD

Abstract

Objective: To 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.
 

Methods: Eight 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.

Results: All 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 <1.33).
 

Conclusions: The 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.

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Authors

William G Mantyh, P James B Dyck,  Peter J Dyck, Janean K Engelstad, William J Litchy, Paola Sandroni, Mark D P Davis

Abstract

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.

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Authors

William G Mantyh, R Robert Auger, Timothy I Morgenthaler, Michael H Silber, Wendy R Moore

Abstract

Authors

Juan M. Jimenez-Andrade,a William G. Mantyh,a Aaron P. Bloom,a Katie T. Freeman,b Joseph R. Ghilardi,b Michael A. Kuskowski,c and Patrick W. Mantyh

Abstract

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) and old (36 month) 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 well as 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.

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Authors

Joseph R Ghilardi, Katie T Freeman, Juan M Jimenez-Andrade, William G Mantyh, Aaron P Bloom, Karyn S Bouhana, David Trollinger, James Winkler, Patrice Lee, Steven W Andrews, Michael A Kuskowski, Patrick W Mantyh

Abstract

Current therapies for treating skeletal pain have significant limitations as available drugs (nonsteroidal anti-inflammatory drugs and opiates) have significant unwanted side effects. Targeting nerve growth factor or it's 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 hours 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, myelinated sensory or 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 & 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 NGF blockade by ARRY-470 are associated with any risks or unexpected effects will be required to fully appreciate the patient populations that may benefit from this therapy.

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Authors

David P Gaus, Diego F Herrera, William G Mantyh, Rajesh P Girdhari, Michael A Kuskowski

Abstract

Objective: 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.

Methods: 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.

Results: 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) (P < 0.001 for each category).

Conclusions: 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.

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Authors

G Castañeda-Corral, J M Jimenez-Andrade, A P Bloom, R N Taylor, W G Mantyh, M J Kaczmarska, J R Ghilardi, P W Mantyh

Abstract

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.

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Authors

Juan Miguel Jimenez-Andrade, William G. Mantyh, Aaron P. Bloom, Kevin Haili Xu, Alice S. Ferng, Gregory Dussor, Todd W. Vanderah, and Patrick W. Mantyh

Abstract

Although musculoskeletal pain is one of the most common causes of chronic pain and physical disability in both developed as well as developing 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 (IB₄) and express the purinergic receptor P₂X₃ 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⁺, P₂X₃⁺ and Mrgprd⁺ sensory nerve fibers, the bone marrow, mineralized bone and periosteum receive a significant innervation by SP⁺ and CGRP⁺, but not Mrgprd⁺ and P₂X₃⁺ 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.

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Authors

Joseph R Ghilardi, Katie T Freeman, Juan M Jimenez-Andrade, William G Mantyh, Aaron P Bloom, Michael A Kuskowski, Patrick W Mantyh

Abstract

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.

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Authors

W G Mantyh, J M Jimenez-Andrade, J I Stake, A P Bloom, M J Kaczmarska, R N Taylor, K T Freeman, J R Ghilardi, M A Kuskowski, P W Mantyh

Abstract

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 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 that therapies blocking this pathological nerve remodeling are initiated, the more effective the control of cancer pain.

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Authors

Juan M Jimenez-Andrade, Aaron P Bloom, James I Stake, William G Mantyh, Reid N Taylor, Katie T Freeman, Joseph R Ghilardi, Michael A Kuskowski, Patrick W Mantyh

Abstract

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.

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Authors

Juan Miguel Jimenez-Andrade, William G. Mantyh, Aaron P. Bloom, Alice S. Ferng, Christopher P. Geffre, and Patrick W. Mantyh

Abstract

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.

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Authors

Juan Miguel Jimenez-Andrade, Aaron P. Bloom, William G. Mantyh, Nathan J. Koewler, Katie T. Freeman, David Delong, Joseph R. Ghilardi, Michael A. Kuskowski, and Patrick W. Mantyh

Abstract

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 kD 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.

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