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IntroductionBehavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments.MethodsA total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation.ResultsParticipants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability.Discussionf-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

IntroductionLeisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD).MethodsA total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans.ResultsGreater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates.DiscussionActive lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Literature series review. `The Elements of Literature (Grades 9-12) Third Course. Fourth Course. Fifth Course. Sixth Course.' Published by Holt, Rinehart and Winston. Includes anthologies, annotated teacher's editions, and teaching portfolios.

Literature series review. Reviews the `Prentice Hall Literature Series' (grades 9-12). Includes a student text, a teacher text, and a teaching portfolio for each grade. Uses Hans Guth's, `The Textbook Gap,' as a guideline for this review.

Background: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown., Objective: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD., Methods: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age., Results: The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases)., Conclusions: These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change., (©Emily W Paolillo, Kaitlin B Casaletto, Annie L Clark, Jack C Taylor, Hilary W Heuer, Amy B Wise, Sreya Dhanam, Mark Sanderson-Cimino, Rowan Saloner, Joel H Kramer, John Kornak, Walter Kremers, Leah Forsberg, Brian Appleby, Ece Bayram, Andrea Bozoki, Danielle Brushaber, R Ryan Darby, Gregory S Day, Bradford C Dickerson, Kimiko Domoto-Reilly, Fanny Elahi, Julie A Fields, Nupur Ghoshal, Neill Graff-Radford, Matthew G H Hall, Lawrence S Honig, Edward D Huey, Maria I Lapid, Irene Litvan, Ian R Mackenzie, Joseph C Masdeu, Mario F Mendez, Carly Mester, Toji Miyagawa, Georges Naasan, Belen Pascual, Peter Pressman, Eliana Marisa Ramos, Katherine P Rankin, Jessica Rexach, Julio C Rojas, Lawren VandeVrede, Bonnie Wong, Zbigniew K Wszolek, Bradley F Boeve, Howard J Rosen, Adam L Boxer, Adam M Staffaroni, ALLFTD Consortium. Originally published in JMIR Aging (https://aging.jmir.org), 26.06.2024.)

Objective: Currently, it is unknown whether infectious prions are present in peripheral tissues and biological fluids of patients affected by sporadic Creutzfeldt-Jakob disease (sCJD), the most common prion disorder in humans. This represents a potential risk for inter-individual prion infection. The main goal of this study was to evaluate the presence of prions in urine of patients suffering from the major subtypes of sCJD., Methods: Urine samples from sCJD patients spanning the six major subtypes were tested. As controls, we used urine samples from people affected by other neurological or neurodegenerative diseases as well as healthy controls. These samples were analyzed blinded. The presence of prions was detected by a modified version of the PMCA technology, specifically optimized for high sensitive detection of sCJD prions., Results: The PMCA assay was first optimized to detect low quantities of prions in diluted brain homogenates from patients affected by all subtypes of sCJD spiked into healthy urine. Twenty-nine of the 81 patients affected by sCJD analyzed in this study were positive by PMCA testing, whereas none of the 160 controls showed any signal. These results indicate a 36% sensitivity and 100% specificity. The subtypes with the highest positivity rate were VV1 and VV2, which combined account for about 15-20% of all sCJD cases, and no detection was observed in MV1 and MM2., Interpretation: Our findings indicate that potentially infectious prions are secreted in urine of some sCJD patients, suggesting a possible risk for inter-individual transmission. Prion detection in urine might be used as a noninvasive preliminary screening test to detect sCJD., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Remote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp)., Methods: A diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD = 0 [ N  = 101]; prodromal: 0.5 [ N  = 49]; symptomatic ≥1 [ N  = 51]; not measured [ N  = 13]) were asked to complete ALLFTD-mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys., Results: It was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests., Discussion: These findings suggest that the ALLFTD-mApp study protocol is feasible and acceptable for remote FTD research., Highlights: The ALLFTD Mobile App is a smartphone-based platform for remote, self-administered data collection.The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities.Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders.Remote digital data collection was well accepted by participants with a variety of diagnoses., Competing Interests: Appleby, BS – receives research support from CDC, NIH, Ionis, Alector, and the CJD Foundation. He has provided consultation to Acadia, Ionis, and Sangamo.Boeve, BF – has served as an investigator for clinical trials sponsored by Alector, Biogen and Transposon. He receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009, 2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, and the Little Family Foundation.Boxer, AL – receives research support from NIH (U19AG063911, R01AG038791, R01AG073482), the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association. He has served as a consultant for Aeovian, AGTC, Alector, Arkuda, Arvinas, AviadoBio, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, Transposon, TrueBinding and Wave, and received research support from Biogen, Eisai, and Regeneron. As a co‐inventor of ALLFTD‐mApp tasks, Dr. Boxer has received licensing fees.Brushaber, D – nothing to disclose.Clark, AL – nothing to disclose.Dickerson, BC – Dr Dickerson is a consultant for Acadia, Alector, Arkuda, Biogen, Denali, Eisai, Genentech, Lilly, Merck, Novartis, Takeda, Wave Lifesciences. Dr Dickerson receives royalties from Cambridge University Press, Elsevier, Oxford University Press. Dr Dickerson receives grant funding from the NIA, NINDS, NIMH, and the Bluefield Foundation.Domoto‐Reilly, K – receives research support from NIH, and serves as an investigator for a clinical trial sponsored by Lawson Health Research Institute.Fields, JA – receives research support from NIH.Forsberg, L – receives research support from NIH.Ghoshal, N – has participated or is currently participating in clinical trials of anti‐dementia drugs sponsored by the following companies: Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) study, and A4 (The Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. She receives research support from Tau Consortium and Association for Frontotemporal Dementia and is funded by the NIH.Gorno‐Tempini, ML – receives research support from NIH. As a co‐inventor of one of the ALLFTD mApp tasks, Dr Gorno‐Tempini's lab receives licensing fees , consistent with UCSF institutional policy.Graff‐Radford, N – receives royalties from UpToDate, has participated in multicenter therapy studies by sponsored by Biogen, TauRx, AbbVie, Novartis, and Lilly. He receives research support from NIH.Grossman, M – receives grant support from NIH, Avid, and Piramal; participates in clinical trials sponsored by Biogen, TauRx, and Alector; serves as a consultant to Bracco and UCB; and serves on the Editorial Board of Neurology.Hall, MGH – nothing to disclose.Heuer, HW – nothing to disclose.Huey, ED – receives research support from NIH.Irwin, D – receives support from NIH, Brightfocus Foundation, and Penn Institute on Aging.Kornak, J – has provided expert witness testimony for Teva Pharmaceuticals in Forest Laboratories Inc. et al. v. Teva Pharmaceuticals USA, Inc., Case Nos. 1:14‐cv‐00121 and 1:14‐cv‐00686 (D. Del. filed Jan. 31, 2014, and May 30, 2014) regarding the drug Memantine; for Apotex/HEC/Ezra in Novartis AG et al. v. Apotex Inc., No. 1:15‐cv‐975 (D. Del. filed Oct. 26, 2015, regarding the drug Fingolimod. He has also given testimony on behalf of Puma Biotechnology in Hsingching Hsu et al, vs. Puma Biotechnology, INC., et al. 2018 regarding the drug Neratinib. He receives research support from the NIH.Kramer, J – receives research support from NIH and royalties from Pearson Inc.Kremers, W—receives research funding from AstraZeneca, Biogen, Roche, DOD, and NIH.Lapid, MI – receives research support from the NIH.Litvan, I – receives research support from the National Institutes of Health grants: 2R01AG038791‐06A, U01NS100610, U01NS80818, R25NS098999; U19 AG063911‐1 and 1R21NS114764‐01A1; the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Centogene. EIP‐Pharma, Biohaven Pharmaceuticals, Novartis, and United Biopharma SRL‐UCB. She is a Scientific advisor for Amydis (Gratis) and Rossy Center for Progressive Supranuclear Palsy University of Toronto. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology.Mackenzie, IR – receives research funding from Canadian Institutes of Health Research, Alzheimer's Association US, NIH, Weston Brain Institute.Manoochehri, M – nothing to disclose.Masdeu, JC – is a consultant and received research funding from Eli Lilly, parent co. of Avid Radiopharmaceuticals, manufacturer of 18F‐flortaucipir, receives personal fees from GE Healthcare, grants and personal fees from Eli Lilly, grants from Acadia, Avanir, Biogen, Eisai, Janssen, NIH, Novartis, with no relation to the submitted work.Mendez, MF – receives research support from NIH.Mester, C – nothing to disclose.Nevler, N – receives research funding from the NIH and Department of Defense.Onyike, C – receives research funding from the NIH, Lawton Health Research Institute, National Ataxia Foundation, Alector Inc., and Transposon, Inc. He is also supported by the Robert and Nancy Hall Brain Research Fund, the Jane Tanger Black Fund for Young‐Onset Dementias, and the gift from Joseph Trovato. He is a consultant with Alector, Inc. and Acadia Pharmaceuticals.Pascual, B – receives research support from NIH.Pressman, PS – receives research support from NIH.Rankin, KP – receives research support from NIH and NSF, and serves on a Medical Advisory Board for Eli Lilly.Rao, M – nothing to disclose.Rojas, JC – receives research support from NIH and is a site PI for clinical trials sponsored by Eli‐Lilly and Eisai.Rosen, HJ – has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from NIH.Ratnasiri, B – nothing to disclose.Staffaroni, AM – received research support from the NIA/NIH, Bluefield Project to Cure FTD, and the Larry L. Hillblom Foundation, and has provided consultation to Alector, Lilly/Prevail, Passage Bio, and Takeda. Dr Staffaroni is a co‐inventor of four ALLFTD mApp tasks and receives licensing fees, consistent with UCSF institutional policy.Tartaglia, M – has served as an investigator for clinical trials sponsored by Biogen, Avanex, Green Valley, and Roche / Genentech, Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen. She receives research support from Canadian Institutes of Health Research. Author disclosures are available in the supporting information.Taylor, JC – nothing to disclose.Wise, AB – nothing to disclose.Welch, AE – nothing to disclose.Wong, B – receives research support from the NIH., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Unlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Field hockey is a high-intensity intermittent team sport that has recently undergone a series of rule changes that have resulted in a greater demand for repeated high-intensity movements. Coaches and practitioners now require a reliable assessment of repeated accelerations, decelerations and changes of direction to assess these important match qualities. This investigation assessed the test-retest reliability of a novel 6x40m repeated shuttle sprint test (20m + 20m with a 180° turn) and its association with 40m straight line sprint and YoYo Intermittent Recovery Test performance in 28 International field hockey players (n = 14 females and n = 14 males). The sum of 6 sprint times (SUM) demonstrated 'excellent' (ICC = 0.94 and CV = 0.59%) and 'good' (ICC = 0.84 and CV = 0.75%) reliability in females and males, respectively. Best sprint time during the repeated shuttle sprint test also demonstrated suitable reliability to evaluate field hockey physical performance (ICC = 0.92 & 0.76, CV = 0.76% & 1.00% in females and males, respectively). SUM was significantly associated with 40 m straight line sprint performance in females (r = 0.90; p<0.001) and males (r = 0.92; p<0.001), but only a weak association was found with YoYo Intermittent Recovery Test performance for either group (r = 0.20; p = 0.495 & r = -0.19; p = 0.525 in females and males, respectively). In summary, field hockey testing batteries that include a repeated shuttle sprint test should consider including a test of intermittent endurance. Further, changes in SUM greater than 1.0% can be confidently interpreted by coaches and practitioners as a real change for both female and male elite field hockey players., Competing Interests: The authors have declared that no competing interests exist.

Definitive diagnosis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) relies on postmortem finding of disease-associated alpha-synuclein (αSyn D ) as misfolded protein aggregates in the central nervous system (CNS). The recent development of the real-time quaking induced conversion (RT-QuIC) assay for ultrasensitive detection of αSyn D aggregates has revitalized the diagnostic values of clinically accessible biospecimens, including cerebrospinal fluid (CSF) and peripheral tissues. However, the current αSyn RT-QuIC assay platforms vary widely and are thus challenging to implement and standardize the measurements of αSyn D across a wide range of biospecimens and in different laboratories. We have streamlined αSyn RT-QuIC assay based on a second generation assay platform that was assembled entirely with commercial reagents. The streamlined RT-QuIC method consisted of a simplified protocol requiring minimal hands-on time, and allowing for a uniform analysis of αSyn D in different types of biospecimens from PD and DLB. Ultrasensitive and specific RT-QuIC detection of αSyn D aggregates was achieved in million-fold diluted brain homogenates and in nanoliters of CSF from PD and DLB cases but not from controls. Comparative analysis revealed higher seeding activity of αSyn D in DLB than PD in both brain homogenates and CSF. Our assay was further validated with CSF samples of 214 neuropathologically confirmed cases from tissue repositories (88 PD, 58 DLB, and 68 controls), yielding a sensitivity of 98% and a specificity of 100%. Finally, a single RT-QuIC assay protocol was employed uniformly to detect seeding activity of αSyn D in PD samples across different types of tissues including the brain, skin, salivary gland, and colon. We anticipate that our streamlined protocol will enable interested laboratories to easily and rapidly implement the αSyn RT-QuIC assay for various clinical specimens from PD and DLB. The utilization of commercial products for all assay components will improve the robustness and standardization of the RT-QuIC assay for diagnostic applications across different sites. Due to ultralow sample consumption, the ultrasensitive RT-QuIC assay will facilitate efficient use and sharing of scarce resources of biospecimens. Our streamlined RT-QuIC assay is suitable to track the distribution of αSyn D in CNS and peripheral tissues of affected patients. The ongoing evaluation of RT-QuIC assay of αSyn D as a potential biomarker for PD and DLB in clinically accessible biospecimens has broad implications for understanding disease pathogenesis, improving early and differential diagnosis, and monitoring therapeutic efficacies in clinical trials.

Background: Prion diseases are a group of lethal neurodegenerative conditions that occur when the normal, cellular form of the prion protein (PrP C ) is converted into an abnormal, scrapie, form of the protein (PrP Sc ). Disease may be caused by genetic, infectious, or sporadic etiologies. The genetic form of prion disease comprises~10%-15% of all cases. Prion disease is typically inherited in an autosomal dominant manner. The low incidence of disease makes it highly unlikely that a patient would have two different pathogenic variants. However, we recently identified a case in which the patient did have two pathogenic PRNP variants and presented with an atypical phenotype., Methods: The patient was evaluated at the Washington Hospital Healthcare System in Fremont, CA. The clinical information for this case report was obtained retrospectively. Variants in the PRNP were identified by polymerase chain reaction (PCR) amplification of exon two of the gene followed by bi-directional sequence analysis. To determine the phase of the identified variants, a restriction enzyme digestion was utilized, followed by sequence analysis of the products. Cerebral spinal fluid (CSF) was analyzed for surrogate markers of prion disease, 14-3-3 and Tau proteins. CSF real-time quaking-induced conversion (RT-QuIC) assays were also performed., Results: The patient was a compound heterozygote for the well-characterized c.628G>A (p.Val210Ile) variant and the rare octapeptide deletion of two repeats [c.202&#95;249del48 (p.P68&#95;Q83del)]. Clinically, the patient presented with an early onset demyelinating peripheral neuropathy, followed by later onset cognitive symptoms., Conclusion: This presentation is reminiscent of prion protein knockout mice whose predominate symptom, due to complete loss of PrP, was late-onset peripheral neuropathy. To our knowledge this is the first case reported of a patient with prion disease who had two different pathogenic variants in PRNP., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Introduction: Conventional Z-scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these "adjusted" Z-scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z-scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency., Methods: In this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance)., Results: Corrected Z-scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted-R 2 ., Discussion: Nonlinearly corrected Z-scores with respect to age, sex, and education with age-varying residual standard deviation allow for improved detection of non-normative extreme cognitive scores., (© 2019 Published by Elsevier Inc. on behalf of the Alzheimer's Association.)

The presence of abnormal, disease-related prion protein (PrP D ) has recently been demonstrated by protein misfolding cyclic amplification (PMCA) in urine of patients affected with variant Creutzfeldt-Jakob disease (vCJD), a prion disease typically acquired from consumption of prion contaminated bovine meat. The complexity and multistage process of urine excretion along with the obligatory use of PMCA raise the issue of whether strain characteristics of the PrP D present in vCJD brains, such as infectivity and phenotype determination, are maintained in urine excreted PrP D and following amplification by PMCA. We inoculated transgenic mice expressing normal human PrP with amplified urine and brain homogenate achieving the same 100% attack rate, similar incubation periods (in both cases extremely long) and histopathological features as for type and severity of the lesions. Furthermore, PrP D characteristics analyzed by immunoblot and conformational stability immunoassay were indistinguishable. Inoculation of raw vCJD urine caused no disease, confirming the extremely low concentration of PrP D in vCJD urine. These findings show that strain characteristics of vCJD brain PrP D , including infectivity, are preserved in PrP D present in urine and are faithfully amplified by means of PMCA; moreover, they suggest that the PrP D urine test might allow for the diagnosis and identification of disease subtype also in sporadic CJD.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive traumatic brain injury (TBI). CTE is generally found in athletes participating in contact sports and military personnel exposed to explosive blasts but can also affect civilians. Clinically and pathologically, CTE overlaps with post-traumatic stress disorder (PTSD), a term mostly used in a clinical context. The histopathology of CTE is defined by the deposition of hyperphosphorylated tau protein in neurons and astrocytes preferentially with perivascular distribution and at the depths of the cortical sulci. In addition to hyperphosphorylated tau, other pathologic proteins are deposited in CTE, including amyloid β (Aβ), transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and α-synuclein. However, the coexistence of prion disease in CTE has not been observed. We report three cases of histopathologically validated CTE with co-existing sporadic prion disease. Two were identified in a cohort of 55 pathologically verified cases of CTE submitted to the CTE Center of Boston University. One was identified among brain tissues submitted to the National Prion Disease Pathology Surveillance Center of Case Western Reserve University. The histopathological phenotype and properties of the abnormal, disease-related prion protein (PrP D ) of the three CTE cases were examined using lesion profile, immunohistochemistry, electrophoresis and conformational tests. Subjects with sporadic Creutzfeldt-Jakob disease (sCJD) matched for age, PrP genotype and PrP D type were used as controls. The histopathology phenotype and PrP D properties of the three CTE subjects showed no significant differences from their respective sCJD controls suggesting that recurring neurotrauma or coexisting CTE pathology did not detectably impact the prion disease phenotype and PrP D conformational characteristics. Based on the reported incidence of sporadic prion disease, the detection of two cases with sCJD in the CTE Center series of 55 CTE cases by chance alone would be highly unlikely (p = 8.93*10 - 6 ). Nevertheless, examination of a larger cohort of CTE is required to conclusively determine whether the risk of CJD is significantly increased in patients with CTE.

Objective: To describe the clinicopathologic, molecular, and transmissible characteristics of genetic prion disease in a young man carrying the PRNP -G114V variant., Methods: We performed genetic, histologic, and molecular studies, combined with in vivo transmission studies and in vitro replication studies, to characterize this genetic prion disease., Results: A 24-year-old American man of Polish descent developed progressive dementia, aphasia, and ataxia, leading to his death 5 years later. Histologic features included widespread spongiform degeneration, gliosis, and infrequent PrP plaque-like deposits within the cerebellum and putamen, best classifying this as a Creutzfeldt-Jakob disease (CJD) subtype. Molecular typing of proteinase K-resistant PrP (resPrP Sc ) revealed a mixture of type 1 (∼21 kDa) and type 2 (∼19 kDa) conformations with only 2, rather than the usual 3, PrP Sc glycoforms. Brain homogenates from the proband failed to transmit prion disease to transgenic Tg(HuPrP) mice that overexpress human PrP and are typically susceptible to sporadic and genetic forms of CJD. When subjected to protein misfolding cyclic amplification, the PrP Sc type 2 (∼19 kDa) was selectively amplified., Conclusions: The features of genetic CJD G114V suggest that residue 114 within the highly conserved palindromic region (113-A G AAAAGA-120) plays an important role in prion conformation and propagation.

Background: In recent years, athletes have ventured into ultra-endurance and adventure racing events, which tests their ability to race, navigate, and survive. These events often require race participants to carry some form of load, to bear equipment for navigation and survival purposes. Previous studies have reported specific alterations in biomechanics when running with load which potentially influence running performance and injury risk. We hypothesize that a biomechanically informed neuromuscular training program would optimize running mechanics during load carriage to a greater extent than a generic strength training program., Methods: This will be a two group, parallel randomized controlled trial design, with single assessor blinding. Thirty healthy runners will be recruited to participate in a six weeks neuromuscular training program. Participants will be randomized into either a generic training group, or a biomechanically informed training group. Primary outcomes include self-determined running velocity with a 20 % body weight load, jump power, hopping leg stiffness, knee extensor and triceps-surae strength. Secondary outcomes include running kinetics and kinematics. Assessments will occur at baseline and post-training., Discussion: To our knowledge, no training programs are available that specifically targets a runner's ability to carry load while running. This will provide sport scientists and coaches with a foundation to base their exercise prescription on., Trial Registration: ANZCTR ( ACTRN12616000023459 ) (14 Jan 2016).

Vast evidence on human prions demonstrates that variable disease phenotypes, rates of propagation, and targeting of distinct brain structures are determined by unique conformers (strains) of pathogenic prion protein (PrP(Sc)). Recent progress in the development of advanced biophysical tools that inventory structural characteristics of amyloid beta (Aβ) in the brain cortex of phenotypically diverse Alzheimer's disease (AD) patients, revealed unique spectrum of oligomeric particles in the cortex of rapidly progressive cases, implicating these structures in variable rates of propagation in the brain, and in distict disease manifestation. Since only ∼30% of phenotypic diversity of AD can be explained by polymorphisms in risk genes, these and transgenic bioassay data argue that structurally distinct Aβ particles play a major role in the diverse pathogenesis of AD, and may behave as distinct prion-like strains encoding diverse phenotypes. From these observations and our growing understanding of prions, there is a critical need for new strain-specific diagnostic strategies for misfolded proteins causing these elusive disorders. Since targeted drug therapy can induce mutation and evolution of prions into new strains, effective treatments of AD will require drugs that enhance clearance of pathogenic conformers, reduce the precursor protein, or inhibit the conversion of precursors into prion-like states.

Aim: To explore health professionals' intentional behaviour and what determines their intention to use products of research in clinical practice., Background: Trying to get research and products of research into clinical practice is an enduring problem. A clearer picture is emerging as to how individual practitioners respond toward practical problems of changing clinical practice, but this does not include health professionals' intentions to use products of research and what influences their intentions., Design: Systematic Review and Narrative Synthesis., Data Sources: Five databases were searched systematically. This included BNI, HMIC, Psych INFO, CINHAL and MEDLINE; articles published in the English language only were included., Review Methods: PRISMA guidelines were used as a framework for structuring the review and methods of narrative synthesis to analyse study outcomes., Results: Eighteen studies matched the final inclusion criteria. All studies used questionnaires to measure intention. Most studies involved Nurses or Physicians. Nurses' intentions were mostly influenced by their perceived ability to use guidelines in their practice. Physicians' intentions were often influenced by their perceptions of the usefulness and relevance of the guideline and peer pressure amongst the professional group. Practice habits, when added to intentional models were also predictive of intentional behaviour. In studies that compared intentions with behaviour, the level of intention often did not match self-report or actual behaviour.

Cervical spine injuries in Rugby Union are a concerning issue at all levels of the game. The primary aim of this retrospective analysis conducted in a professional Rugby Union squad was to determine whether a 26-week isometric neck strengthening intervention program (13-week strengthening phase and 13-week maintenance phase) was effective in reducing the number and severity of cervical spine injuries. The secondary aim was to determine whether at week five, where the program had been the similar for all players, there was increased isometric neck strength. All 27 players who were common to both the 2007-2008 and 2008-2009 seasons were included in this analysis and data was extracted from a Sports Medicine/Sports Science database which included the squad's injury records. Primary outcome variables included; the number of cervical spine injuries and the severity of these injuries as determined by the total number of days lost from training and competition. Secondary outcome variables included isometric neck strength in flexion, extension and left and right lateral flexion. Using non-parametric statistical methods, no significant differences were evident for the total number of cervical spine injuries (n = 8 in 2007-2008, n = 6 in 2008-2009) or time loss due to these injuries (100 days in 2007-2008, 40 days in 2008-2009). However, a significant (p = 0.03) reduction in the number of match injuries was evident from 2007-2008 (n = 11) to 2008-09 (n = 2). Non-significant increases in isometric neck strength were found in all directions examined. A significant reduction in the number of match injuries was evident in this study. However, no other significant changes to primary outcome variables were achieved. Further, no significant increases in isometric neck strength were found in this well-trained group of professional athletes. Key PointsWhile many authors have proposed that neck strengthening could be an effective strategy in preventing cervical spine injuries in Rugby Union, there is currently little information in the literature pertaining to how such a study might be conducted.A significant decrease in the number of injuries recorded in matches can be achieved using a specific neck strengthening program at the elite level.In an elite rugby union team as investigated in this study a significant increase in neck strength is difficult to achieve in a short period of time such as five weeks.