FDA Approves Test of New Drug to Protect Hearing

The first clinical trial of a new drug designed to protect humans' hearing will involve a compound developed at the University of Washington (UW).

The U.S. Food and Drug Administration has approved ORC-13661 as an investigational drug to protect people from the hearing-damaging side effects of aminoglycosides, a class of antibiotics used to combat serious infections.  The FDA approval clears the way for a Phase I trial of volunteers to confirm whether the drug, which demonstrated significant protective ability in animal models, is safe for humans.

ORC-13661 represents more than a decade of work by two UW scientists: Edwin Rubel, a professor of hearing sciences in the departments of otolaryngology-head and neck surgery and physiology & biophysics, and David Raible, a professor of biological structure in the School of Medicine.

"Our collaboration started in 2001; it was a novel idea and we got funded," Rubel said. "The goal was to discover how the receptor cells in the inner ear die. Why do some people start to lose their hearing at age 40 and others have good hearing at age 80?"

Their study of zebrafish was pivotal to understanding the mechanisms that affect hearing in humans. Fish have external hair cells akin to the receptor-cell structures in humans' cochleas, which turn sound waves into electrical impulses for the brain to interpret.

"With the hair cells on the outside of their bodies, we could observe them very readily for genetic and molecular studies," Rubel said.

Human receptor cells can be damaged as a secondary effect of antibiotics called aminoglycosides, which doctors employ against severe infections in cases of cystic fibrosis, immune suppression, and premature newborns, among other conditions. These powerul antibiotics – for example, gentamicin and streptomycin – can kill the receptor cells in the cochlea and balance organs, causing permanent hearing loss and unsteadiness for patients.

Over 16 years, Rubel and Raible confirmed that the fishes' hair cells are similar genetically and in other ways to hearing receptor cells in humans and other mammals.

In concert with Julian Simon, a medicinal chemist based at the Fred Hutchinson Cancer Research Center, and others, they tested the ability of more than 10,000 molecules to protect the zebrafishes' hair cells from the toxic effects of these antibiotics.

"We did a phenotypic screen," said Raible. "It's a different approach from many drug screens that target a specific receptor or protein known to be important, and then design a molecule to fit the active site of the protein. Instead, we screened libraries of chemicals to find ones that stopped zebrafish hair cells from dying, and used the one that worked best. But we can't say we know exactly why it works."

Their breakthrough results, published last month, involved a change that amplified the effectiveness of a promising compound from earlier studies. The drug demonstrated outstanding safety and 100-percent protection of hair cells in zebrafish and rats in vivo. This spurred the FDA's action.

In 2013 Raible and Rubel co-founded a company, Oricula Therapeutics, which exclusively licenses patents for ORC-13661 held by the University of Washington and Fred Hutch.  Oricula made the application to the FDA and will pursue funding for the Phase I trial of the drug's safety in humans, Rubel said. If that were to succeed, the next step would be testing the drug's effectiveness among patients who must take aminoglycosides to stave off life-threatening infections.

Both scientists reflected on the infusion of $34,000 that got them going back in 2001. The money came from the UW's Royalty Research Fund, a mechanism in which UW's royalty and licensing fee income is selectively reinvested in promising new research.

"It's such a cool thing that the university uses royalties to seed new ideas that might one day reinfuse the fund," Raible said. "The people who came up with the fund should know that it does make a difference in these ventures."

This news original appeared in the UW Medicine Newsroom.

Published: 2/6/2018 1:09:00 PM

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FDA Approves Test of New Drug to Protect Hearing

The first clinical trial of a new drug designed to protect humans' hearing will involve a compound developed at the University of Washington (UW).

The U.S. Food and Drug Administration has approved ORC-13661 as an investigational drug to protect people from the hearing-damaging side effects of aminoglycosides, a class of antibiotics used to combat serious infections.  The FDA approval clears the way for a Phase I trial of volunteers to confirm whether the drug, which demonstrated significant protective ability in animal models, is safe for humans.

ORC-13661 represents more than a decade of work by two UW scientists: Edwin Rubel, a professor of hearing sciences in the departments of otolaryngology-head and neck surgery and physiology & biophysics, and David Raible, a professor of biological structure in the School of Medicine.

"Our collaboration started in 2001; it was a novel idea and we got funded," Rubel said. "The goal was to discover how the receptor cells in the inner ear die. Why do some people start to lose their hearing at age 40 and others have good hearing at age 80?"

Their study of zebrafish was pivotal to understanding the mechanisms that affect hearing in humans. Fish have external hair cells akin to the receptor-cell structures in humans' cochleas, which turn sound waves into electrical impulses for the brain to interpret.

"With the hair cells on the outside of their bodies, we could observe them very readily for genetic and molecular studies," Rubel said.

Human receptor cells can be damaged as a secondary effect of antibiotics called aminoglycosides, which doctors employ against severe infections in cases of cystic fibrosis, immune suppression, and premature newborns, among other conditions. These powerul antibiotics – for example, gentamicin and streptomycin – can kill the receptor cells in the cochlea and balance organs, causing permanent hearing loss and unsteadiness for patients.

Over 16 years, Rubel and Raible confirmed that the fishes' hair cells are similar genetically and in other ways to hearing receptor cells in humans and other mammals.

In concert with Julian Simon, a medicinal chemist based at the Fred Hutchinson Cancer Research Center, and others, they tested the ability of more than 10,000 molecules to protect the zebrafishes' hair cells from the toxic effects of these antibiotics.

"We did a phenotypic screen," said Raible. "It's a different approach from many drug screens that target a specific receptor or protein known to be important, and then design a molecule to fit the active site of the protein. Instead, we screened libraries of chemicals to find ones that stopped zebrafish hair cells from dying, and used the one that worked best. But we can't say we know exactly why it works."

Their breakthrough results, published last month, involved a change that amplified the effectiveness of a promising compound from earlier studies. The drug demonstrated outstanding safety and 100-percent protection of hair cells in zebrafish and rats in vivo. This spurred the FDA's action.

In 2013 Raible and Rubel co-founded a company, Oricula Therapeutics, which exclusively licenses patents for ORC-13661 held by the University of Washington and Fred Hutch.  Oricula made the application to the FDA and will pursue funding for the Phase I trial of the drug's safety in humans, Rubel said. If that were to succeed, the next step would be testing the drug's effectiveness among patients who must take aminoglycosides to stave off life-threatening infections.

Both scientists reflected on the infusion of $34,000 that got them going back in 2001. The money came from the UW's Royalty Research Fund, a mechanism in which UW's royalty and licensing fee income is selectively reinvested in promising new research.

"It's such a cool thing that the university uses royalties to seed new ideas that might one day reinfuse the fund," Raible said. "The people who came up with the fund should know that it does make a difference in these ventures."

This news original appeared in the UW Medicine Newsroom.

Published: 2/6/2018 1:09:00 PM

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FDA Approves Test of New Drug to Protect Hearing

The first clinical trial of a new drug designed to protect humans' hearing will involve a compound developed at the University of Washington (UW).

The U.S. Food and Drug Administration has approved ORC-13661 as an investigational drug to protect people from the hearing-damaging side effects of aminoglycosides, a class of antibiotics used to combat serious infections.  The FDA approval clears the way for a Phase I trial of volunteers to confirm whether the drug, which demonstrated significant protective ability in animal models, is safe for humans.

ORC-13661 represents more than a decade of work by two UW scientists: Edwin Rubel, a professor of hearing sciences in the departments of otolaryngology-head and neck surgery and physiology & biophysics, and David Raible, a professor of biological structure in the School of Medicine.

"Our collaboration started in 2001; it was a novel idea and we got funded," Rubel said. "The goal was to discover how the receptor cells in the inner ear die. Why do some people start to lose their hearing at age 40 and others have good hearing at age 80?"

Their study of zebrafish was pivotal to understanding the mechanisms that affect hearing in humans. Fish have external hair cells akin to the receptor-cell structures in humans' cochleas, which turn sound waves into electrical impulses for the brain to interpret.

"With the hair cells on the outside of their bodies, we could observe them very readily for genetic and molecular studies," Rubel said.

Human receptor cells can be damaged as a secondary effect of antibiotics called aminoglycosides, which doctors employ against severe infections in cases of cystic fibrosis, immune suppression, and premature newborns, among other conditions. These powerul antibiotics – for example, gentamicin and streptomycin – can kill the receptor cells in the cochlea and balance organs, causing permanent hearing loss and unsteadiness for patients.

Over 16 years, Rubel and Raible confirmed that the fishes' hair cells are similar genetically and in other ways to hearing receptor cells in humans and other mammals.

In concert with Julian Simon, a medicinal chemist based at the Fred Hutchinson Cancer Research Center, and others, they tested the ability of more than 10,000 molecules to protect the zebrafishes' hair cells from the toxic effects of these antibiotics.

"We did a phenotypic screen," said Raible. "It's a different approach from many drug screens that target a specific receptor or protein known to be important, and then design a molecule to fit the active site of the protein. Instead, we screened libraries of chemicals to find ones that stopped zebrafish hair cells from dying, and used the one that worked best. But we can't say we know exactly why it works."

Their breakthrough results, published last month, involved a change that amplified the effectiveness of a promising compound from earlier studies. The drug demonstrated outstanding safety and 100-percent protection of hair cells in zebrafish and rats in vivo. This spurred the FDA's action.

In 2013 Raible and Rubel co-founded a company, Oricula Therapeutics, which exclusively licenses patents for ORC-13661 held by the University of Washington and Fred Hutch.  Oricula made the application to the FDA and will pursue funding for the Phase I trial of the drug's safety in humans, Rubel said. If that were to succeed, the next step would be testing the drug's effectiveness among patients who must take aminoglycosides to stave off life-threatening infections.

Both scientists reflected on the infusion of $34,000 that got them going back in 2001. The money came from the UW's Royalty Research Fund, a mechanism in which UW's royalty and licensing fee income is selectively reinvested in promising new research.

"It's such a cool thing that the university uses royalties to seed new ideas that might one day reinfuse the fund," Raible said. "The people who came up with the fund should know that it does make a difference in these ventures."

This news original appeared in the UW Medicine Newsroom.

Published: 2/6/2018 1:09:00 PM

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AudioNotch: Notched Sound Therapy for Tinnitus

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Effects of AUT00063, a Kv3.1 channel modulator, on noise-induced hyperactivity in the dorsal cochlear nucleus

Publication date: Available online 7 February 2018
Source:Hearing Research
Author(s): Lyall Glait, Weiwen Fan, Gina Stillitano, Sharon Sandridge, Nadia Pilati, Charles Large, Giuseppe Alvaro, James A. Kaltenbach
The purpose of this study was to test whether a Kv3 potassium channel modulator, AUT00063, has therapeutic potential for reversing noise-induced increases in spontaneous neural activity, a state that is widely believed to underlie noise-induced tinnitus. Recordings were conducted in noise exposed and control hamsters from dorsal cochlear nucleus (DCN) fusiform cells before and following intraperitoneal administration of AUT00063 (30 mg/kg). Fusiform cell spontaneous activity was increased in sound-exposed animals, approximating levels that were nearly 50% above those of controls. Administration of AUT00063 resulted in a powerful suppression of this hyperactivity. The first signs of this suppression began 13 min after AUT00063 administration, but activity continued to decline gradually until reaching a floor level which was approximately 60% of pre-drug baseline by 25 min after drug treatment. A similar suppressive effect of AUT00063 was observed in control animals, with onset of suppression first apparent at 13 min post-treatment, but continuing to decline toward a plateau that was 54% of pre-drug baseline and was reached 28 min after drug treatment. In contrast, no suppression of spontaneous activity was observed in animals given similar injections of vehicle (control) solution. The suppressive effect of AUT00063 was achieved without significantly altering heart rate and with minimal effects on response thresholds, supporting the interpretation that the reductions of hyperactivity were not a secondary consequence of a more general physiological suppression of the brain or auditory system. These findings suggest that Kv3 channel modulation may be an effective approach to suppressing spontaneous activity in the auditory system and may provide a future avenue for treatment of tinnitus resulting from exposure to intense sound.



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Effects of AUT00063, a Kv3.1 channel modulator, on noise-induced hyperactivity in the dorsal cochlear nucleus

Publication date: Available online 7 February 2018
Source:Hearing Research
Author(s): Lyall Glait, Weiwen Fan, Gina Stillitano, Sharon Sandridge, Nadia Pilati, Charles Large, Giuseppe Alvaro, James A. Kaltenbach
The purpose of this study was to test whether a Kv3 potassium channel modulator, AUT00063, has therapeutic potential for reversing noise-induced increases in spontaneous neural activity, a state that is widely believed to underlie noise-induced tinnitus. Recordings were conducted in noise exposed and control hamsters from dorsal cochlear nucleus (DCN) fusiform cells before and following intraperitoneal administration of AUT00063 (30 mg/kg). Fusiform cell spontaneous activity was increased in sound-exposed animals, approximating levels that were nearly 50% above those of controls. Administration of AUT00063 resulted in a powerful suppression of this hyperactivity. The first signs of this suppression began 13 min after AUT00063 administration, but activity continued to decline gradually until reaching a floor level which was approximately 60% of pre-drug baseline by 25 min after drug treatment. A similar suppressive effect of AUT00063 was observed in control animals, with onset of suppression first apparent at 13 min post-treatment, but continuing to decline toward a plateau that was 54% of pre-drug baseline and was reached 28 min after drug treatment. In contrast, no suppression of spontaneous activity was observed in animals given similar injections of vehicle (control) solution. The suppressive effect of AUT00063 was achieved without significantly altering heart rate and with minimal effects on response thresholds, supporting the interpretation that the reductions of hyperactivity were not a secondary consequence of a more general physiological suppression of the brain or auditory system. These findings suggest that Kv3 channel modulation may be an effective approach to suppressing spontaneous activity in the auditory system and may provide a future avenue for treatment of tinnitus resulting from exposure to intense sound.



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Effects of AUT00063, a Kv3.1 channel modulator, on noise-induced hyperactivity in the dorsal cochlear nucleus

Publication date: Available online 7 February 2018
Source:Hearing Research
Author(s): Lyall Glait, Weiwen Fan, Gina Stillitano, Sharon Sandridge, Nadia Pilati, Charles Large, Giuseppe Alvaro, James A. Kaltenbach
The purpose of this study was to test whether a Kv3 potassium channel modulator, AUT00063, has therapeutic potential for reversing noise-induced increases in spontaneous neural activity, a state that is widely believed to underlie noise-induced tinnitus. Recordings were conducted in noise exposed and control hamsters from dorsal cochlear nucleus (DCN) fusiform cells before and following intraperitoneal administration of AUT00063 (30 mg/kg). Fusiform cell spontaneous activity was increased in sound-exposed animals, approximating levels that were nearly 50% above those of controls. Administration of AUT00063 resulted in a powerful suppression of this hyperactivity. The first signs of this suppression began 13 min after AUT00063 administration, but activity continued to decline gradually until reaching a floor level which was approximately 60% of pre-drug baseline by 25 min after drug treatment. A similar suppressive effect of AUT00063 was observed in control animals, with onset of suppression first apparent at 13 min post-treatment, but continuing to decline toward a plateau that was 54% of pre-drug baseline and was reached 28 min after drug treatment. In contrast, no suppression of spontaneous activity was observed in animals given similar injections of vehicle (control) solution. The suppressive effect of AUT00063 was achieved without significantly altering heart rate and with minimal effects on response thresholds, supporting the interpretation that the reductions of hyperactivity were not a secondary consequence of a more general physiological suppression of the brain or auditory system. These findings suggest that Kv3 channel modulation may be an effective approach to suppressing spontaneous activity in the auditory system and may provide a future avenue for treatment of tinnitus resulting from exposure to intense sound.



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Editorial Board

Publication date: February 2018
Source:Gait & Posture, Volume 60





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β-amyloid deposition is Associated with Gait variability in Usual Aging

Publication date: Available online 6 February 2018
Source:Gait & Posture
Author(s): Qu Tian, Woei-Nan Bair, Susan M. Resnick, Murat Bilgel, Dean F. Wong, Stephanie A. Studenski
BackgroundHigher amyloid burden predicts gait slowing in aging. Whether and which gait characteristics are associated with amyloid burden is less clear. Gait variability may be more sensitive to amyloid burden than mean gait characteristics.MethodsIn the Baltimore Longitudinal Study of Aging, 99 older participants without neurological disease had concurrent amyloid imaging and assessment of gait characteristics. β-amyloid burden was measured using ¹¹C-Pittsburgh compound B (PiB) positron emission tomography. PiB+/− status was based on a mean cortical distribution volume ratio (DVR) cut point. Gait characteristics were quantified by 3D motion analysis. Cross-sectional associations of PiB+/− status and DVR in motor-related regions (primary motor cortex, putamen, caudate) with gait characteristics were examined using linear regression, adjusted for age, sex, height, body mass index, gait speed and covariates (memory, executive function, visuoperceptual speed, depressive symptoms, cardiovascular risk, ApoE ε4, cerebrovascular burden, neurodegeneration, peripheral arterial disease, knee pain).ResultsBeing PiB+ and higher DVR in motor-related regions were associated with greater gait speed variability, cadence variability, and gait cycle time variability but not with mean gait characteristics. Associations remained similar after adjustment for gait speed and covariates, except for memory, which attenuated associations of PiB+/− with cadence variability and gait cycle time variability. Associations were prominent in men but were not found in women.ConclusionsIn usual aging, integrated temporal gait variability measures, but not mean performance, appear related to amyloid burden from cortical and motor-related cortical and subcortical regions, especially in men. Increased gait variability may be a subclinical indicator of increased amyloid burden in men.



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A systematic review of approaches to modelling lower limb muscle forces during gait: applicability to clinical gait analyses

Publication date: Available online 6 February 2018
Source:Gait & Posture
Author(s): Ursula Tinler, Kristen Hollands, Richard Jones, Richard Baker
Computational methods to estimate muscle forces during walking are becoming more common in biomechanical research but not yet in clinical gait analysis. This systematic review aims to identify the current state-of-the-art, examine the differences between approaches, and consider applicability of the current approaches in clinical gait analysis.A systematic database search identified studies including estimated muscle force profiles of the lower limb during healthy walking. These were rated for quality and the muscle force profiles digitised for comparison.From 13.449 identified studies, 22 were finally included which used four modelling approaches: static optimisation, enhanced static optimisation, forward dynamics and EMG-driven. These used a range of different musculoskeletal models, muscle-tendon characteristics and cost functions. There is visually broad agreement between and within approaches about when muscles are active throughout the gait cycle. There remain, considerable differences (CV 7%–151%, range of timing of peak forces in gait cycle 1%–31%) in patterns and magnitudes of force between and within modelling approaches.The main source of this variability is not clear. Different musculoskeletal models, experimental protocols, and modelling approaches will clearly have an effect as will the variability of joint kinetics between healthy individuals. Limited validation of modelling approaches, particularly at the level of individual participants, makes it difficult to conclude if any of the approaches give consistently better estimates than others.While muscle force modelling has clear potential to enhance clinical gait analyses future research is needed to improve validation, accuracy and feasibility of implementation in clinical practice.



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Editorial Board

Publication date: February 2018
Source:Gait & Posture, Volume 60





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β-amyloid deposition is Associated with Gait variability in Usual Aging

Publication date: Available online 6 February 2018
Source:Gait & Posture
Author(s): Qu Tian, Woei-Nan Bair, Susan M. Resnick, Murat Bilgel, Dean F. Wong, Stephanie A. Studenski
BackgroundHigher amyloid burden predicts gait slowing in aging. Whether and which gait characteristics are associated with amyloid burden is less clear. Gait variability may be more sensitive to amyloid burden than mean gait characteristics.MethodsIn the Baltimore Longitudinal Study of Aging, 99 older participants without neurological disease had concurrent amyloid imaging and assessment of gait characteristics. β-amyloid burden was measured using ¹¹C-Pittsburgh compound B (PiB) positron emission tomography. PiB+/− status was based on a mean cortical distribution volume ratio (DVR) cut point. Gait characteristics were quantified by 3D motion analysis. Cross-sectional associations of PiB+/− status and DVR in motor-related regions (primary motor cortex, putamen, caudate) with gait characteristics were examined using linear regression, adjusted for age, sex, height, body mass index, gait speed and covariates (memory, executive function, visuoperceptual speed, depressive symptoms, cardiovascular risk, ApoE ε4, cerebrovascular burden, neurodegeneration, peripheral arterial disease, knee pain).ResultsBeing PiB+ and higher DVR in motor-related regions were associated with greater gait speed variability, cadence variability, and gait cycle time variability but not with mean gait characteristics. Associations remained similar after adjustment for gait speed and covariates, except for memory, which attenuated associations of PiB+/− with cadence variability and gait cycle time variability. Associations were prominent in men but were not found in women.ConclusionsIn usual aging, integrated temporal gait variability measures, but not mean performance, appear related to amyloid burden from cortical and motor-related cortical and subcortical regions, especially in men. Increased gait variability may be a subclinical indicator of increased amyloid burden in men.



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A systematic review of approaches to modelling lower limb muscle forces during gait: applicability to clinical gait analyses

Publication date: Available online 6 February 2018
Source:Gait & Posture
Author(s): Ursula Tinler, Kristen Hollands, Richard Jones, Richard Baker
Computational methods to estimate muscle forces during walking are becoming more common in biomechanical research but not yet in clinical gait analysis. This systematic review aims to identify the current state-of-the-art, examine the differences between approaches, and consider applicability of the current approaches in clinical gait analysis.A systematic database search identified studies including estimated muscle force profiles of the lower limb during healthy walking. These were rated for quality and the muscle force profiles digitised for comparison.From 13.449 identified studies, 22 were finally included which used four modelling approaches: static optimisation, enhanced static optimisation, forward dynamics and EMG-driven. These used a range of different musculoskeletal models, muscle-tendon characteristics and cost functions. There is visually broad agreement between and within approaches about when muscles are active throughout the gait cycle. There remain, considerable differences (CV 7%–151%, range of timing of peak forces in gait cycle 1%–31%) in patterns and magnitudes of force between and within modelling approaches.The main source of this variability is not clear. Different musculoskeletal models, experimental protocols, and modelling approaches will clearly have an effect as will the variability of joint kinetics between healthy individuals. Limited validation of modelling approaches, particularly at the level of individual participants, makes it difficult to conclude if any of the approaches give consistently better estimates than others.While muscle force modelling has clear potential to enhance clinical gait analyses future research is needed to improve validation, accuracy and feasibility of implementation in clinical practice.



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Editorial Board

Publication date: February 2018
Source:Gait & Posture, Volume 60





from #Audiology via ola Kala on Inoreader http://ift.tt/2ErCYOU
via IFTTT

β-amyloid deposition is Associated with Gait variability in Usual Aging

Publication date: Available online 6 February 2018
Source:Gait & Posture
Author(s): Qu Tian, Woei-Nan Bair, Susan M. Resnick, Murat Bilgel, Dean F. Wong, Stephanie A. Studenski
BackgroundHigher amyloid burden predicts gait slowing in aging. Whether and which gait characteristics are associated with amyloid burden is less clear. Gait variability may be more sensitive to amyloid burden than mean gait characteristics.MethodsIn the Baltimore Longitudinal Study of Aging, 99 older participants without neurological disease had concurrent amyloid imaging and assessment of gait characteristics. β-amyloid burden was measured using ¹¹C-Pittsburgh compound B (PiB) positron emission tomography. PiB+/− status was based on a mean cortical distribution volume ratio (DVR) cut point. Gait characteristics were quantified by 3D motion analysis. Cross-sectional associations of PiB+/− status and DVR in motor-related regions (primary motor cortex, putamen, caudate) with gait characteristics were examined using linear regression, adjusted for age, sex, height, body mass index, gait speed and covariates (memory, executive function, visuoperceptual speed, depressive symptoms, cardiovascular risk, ApoE ε4, cerebrovascular burden, neurodegeneration, peripheral arterial disease, knee pain).ResultsBeing PiB+ and higher DVR in motor-related regions were associated with greater gait speed variability, cadence variability, and gait cycle time variability but not with mean gait characteristics. Associations remained similar after adjustment for gait speed and covariates, except for memory, which attenuated associations of PiB+/− with cadence variability and gait cycle time variability. Associations were prominent in men but were not found in women.ConclusionsIn usual aging, integrated temporal gait variability measures, but not mean performance, appear related to amyloid burden from cortical and motor-related cortical and subcortical regions, especially in men. Increased gait variability may be a subclinical indicator of increased amyloid burden in men.



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A systematic review of approaches to modelling lower limb muscle forces during gait: applicability to clinical gait analyses

Publication date: Available online 6 February 2018
Source:Gait & Posture
Author(s): Ursula Tinler, Kristen Hollands, Richard Jones, Richard Baker
Computational methods to estimate muscle forces during walking are becoming more common in biomechanical research but not yet in clinical gait analysis. This systematic review aims to identify the current state-of-the-art, examine the differences between approaches, and consider applicability of the current approaches in clinical gait analysis.A systematic database search identified studies including estimated muscle force profiles of the lower limb during healthy walking. These were rated for quality and the muscle force profiles digitised for comparison.From 13.449 identified studies, 22 were finally included which used four modelling approaches: static optimisation, enhanced static optimisation, forward dynamics and EMG-driven. These used a range of different musculoskeletal models, muscle-tendon characteristics and cost functions. There is visually broad agreement between and within approaches about when muscles are active throughout the gait cycle. There remain, considerable differences (CV 7%–151%, range of timing of peak forces in gait cycle 1%–31%) in patterns and magnitudes of force between and within modelling approaches.The main source of this variability is not clear. Different musculoskeletal models, experimental protocols, and modelling approaches will clearly have an effect as will the variability of joint kinetics between healthy individuals. Limited validation of modelling approaches, particularly at the level of individual participants, makes it difficult to conclude if any of the approaches give consistently better estimates than others.While muscle force modelling has clear potential to enhance clinical gait analyses future research is needed to improve validation, accuracy and feasibility of implementation in clinical practice.



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