HD Insights recognized three papers from 2016 with awards.
Flavia Niccolini of King's College London won for "Altered PDE10A Expression Detectable Early Before Symptomatic Onset in Huntington's Disease."
Jong-Min Lee of the GeM-HD Consortium, won for "Genetic Modifiers of HD"
This document summarizes results from the PRIDE-HD clinical trial of the drug pridopidine for Huntington's disease. The trial involved 437 patients across multiple countries and clinical sites. Key results included:
- Pridopidine did not show a significant effect on total motor score at 26 weeks, though some improvement was seen.
- Pridopidine showed a significant slowing of functional decline as measured by Total Functional Capacity (TFC) at 52 weeks, particularly in early stage patients.
- Responder analysis found more early stage patients on pridopidine maintained or improved TFC scores compared to placebo.
- Safety analysis found no new safety issues, though some psychiatric events were
Healthcare is undergoing a technological transformation, and it is imperative for the industry to leverage new technologies to generate, collect, and track novel data. Panel chaired by Ralf Reilmann of the George Huntington Institut, Muenster.
Neuroimaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have provided important advances in our understanding of Huntington's disease and may be a suitable biomarker for monitoring disease progression in HD and for assessing the efficacy of future disease modifying therapies.
Understanding patient-reported outcome measures in Huntington disease: at wha...Huntington Study Group
Understanding patient-reported outcome measures in Huntington disease: at what point is cognitive impairment related to poor measurement reliability, presented by Nicole Carlozo, PhD, University of Michigan, HSG 2016
- Ocrelizumab (OCR) significantly reduced disability progression and disease activity in patients with primary progressive multiple sclerosis (PPMS) compared to placebo in the ORATORIO clinical trial.
- Evaluation of efficacy in subgroups of patients with and without T1 gadolinium-enhancing (Gd+) lesions at baseline was a key objective. OCR reduced disability progression and disease activity in both subgroups.
- Specifically, OCR reduced the risk of 12-week and 24-week confirmed disability progression by 24-25% in the overall population and in both subgroups. It also reduced the worsening of walking ability and brain lesion volume over 120 weeks compared to placebo.
1) A phase 3 clinical trial evaluated the efficacy of ocrelizumab in reducing disability progression in patients with primary progressive multiple sclerosis (PPMS) with and without T1 gadolinium-enhancing lesions at baseline.
2) Results showed that ocrelizumab reduced the risk of 12-week and 24-week confirmed disability progression by 24% and 25% respectively compared to placebo in the overall study population.
3) When analyzing subgroups based on presence of T1 lesions at baseline, ocrelizumab reduced risk of disability progression in both subgroups, though the results did not reach statistical significance in the subgroup with lesions at baseline.
This document summarizes results from the PRIDE-HD clinical trial of the drug pridopidine for Huntington's disease. The trial involved 437 patients across multiple countries and clinical sites. Key results included:
- Pridopidine did not show a significant effect on total motor score at 26 weeks, though some improvement was seen.
- Pridopidine showed a significant slowing of functional decline as measured by Total Functional Capacity (TFC) at 52 weeks, particularly in early stage patients.
- Responder analysis found more early stage patients on pridopidine maintained or improved TFC scores compared to placebo.
- Safety analysis found no new safety issues, though some psychiatric events were
Healthcare is undergoing a technological transformation, and it is imperative for the industry to leverage new technologies to generate, collect, and track novel data. Panel chaired by Ralf Reilmann of the George Huntington Institut, Muenster.
Neuroimaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have provided important advances in our understanding of Huntington's disease and may be a suitable biomarker for monitoring disease progression in HD and for assessing the efficacy of future disease modifying therapies.
Understanding patient-reported outcome measures in Huntington disease: at wha...Huntington Study Group
Understanding patient-reported outcome measures in Huntington disease: at what point is cognitive impairment related to poor measurement reliability, presented by Nicole Carlozo, PhD, University of Michigan, HSG 2016
- Ocrelizumab (OCR) significantly reduced disability progression and disease activity in patients with primary progressive multiple sclerosis (PPMS) compared to placebo in the ORATORIO clinical trial.
- Evaluation of efficacy in subgroups of patients with and without T1 gadolinium-enhancing (Gd+) lesions at baseline was a key objective. OCR reduced disability progression and disease activity in both subgroups.
- Specifically, OCR reduced the risk of 12-week and 24-week confirmed disability progression by 24-25% in the overall population and in both subgroups. It also reduced the worsening of walking ability and brain lesion volume over 120 weeks compared to placebo.
1) A phase 3 clinical trial evaluated the efficacy of ocrelizumab in reducing disability progression in patients with primary progressive multiple sclerosis (PPMS) with and without T1 gadolinium-enhancing lesions at baseline.
2) Results showed that ocrelizumab reduced the risk of 12-week and 24-week confirmed disability progression by 24% and 25% respectively compared to placebo in the overall study population.
3) When analyzing subgroups based on presence of T1 lesions at baseline, ocrelizumab reduced risk of disability progression in both subgroups, though the results did not reach statistical significance in the subgroup with lesions at baseline.
This document provides information on diagnosing Huntington's disease (HD). It discusses the clinical features of HD including motor dysfunction such as chorea, cognitive impairment, and psychiatric features. The diagnostic evaluation for patients with a family history of HD or symptoms is described, including use of the Unified Huntington's Disease Rating Scale. Differential diagnoses for chorea are also reviewed, including other genetic, metabolic, autoimmune, and drug-induced causes. Workup of patients with chorea may include blood tests, imaging, and genetic testing.
- The study compared ocrelizumab (OCR) to placebo in treating primary progressive multiple sclerosis (PPMS) over approximately 3 years. Baseline characteristics were balanced between the treatment groups.
- OCR met the primary endpoint of reducing disability progression confirmed at 12 weeks compared to placebo. Key secondary endpoints including disability progression at 24 weeks, timed walking test, brain lesion volume, and brain volume loss were also significantly improved by OCR compared to placebo.
- Adverse events including infections were more common with OCR, but serious adverse events and discontinuation due to adverse events were similar between groups. Safety analyses are ongoing given a higher number of reported cancers with OCR, but differences must be considered in
Actrims 2016 opera poster hauser_p024 (1)BartsMSBlog
The document summarizes results from two Phase III clinical trials called OPERA I and OPERA II that compared the efficacy and safety of ocrelizumab (OCR) to interferon beta-1a (IFN β-1a) in patients with relapsing multiple sclerosis (RMS). Key results include:
1) OCR significantly reduced annualized relapse rates (ARR) by 46-47% compared to IFN β-1a in both studies. OCR also reduced disability progression and brain lesion activity to a greater extent than IFN β-1a.
2) A higher proportion of patients on OCR achieved no evidence of disease activity compared to those on IFN β-1a.
Safety and Efficacy of Low Dose versus Standard Dose of Alteplase for Stroke Thrombolysis in Hospital Sultanah Nur Zahirah (HSNZ)
Presentation Slides by Ms Mahfuzah Ishak, presented on the 14th National Conference for Clinical Research (NCCR) 2021 Dr Wu Lien Teh Youth Investigator Awards (YIA) on 19th August 2021
Following are the links for this presentation on Zenodo Repository:
Presentation Slides: https://zenodo.org/record/5348496
E-Poster: https://zenodo.org/record/5348723
Associated Factors of Stroke Severity Among Young Adult Stroke Patients in Malaysia from National Neurology Registry 2014 - 2018
Presentation Slides by Ms Fara Waheda Jusoh, presented on the 14th National Conference for Clinical Research (NCCR) 2021 Dr Wu Lien Teh Youth Investigator Awards (YIA) on 19th August 2021
Following are the links for this presentation on Zenodo Repository:
Presentation Slides: https://zenodo.org/record/5348488
E-Poster: https://zenodo.org/record/5348580
2014-10-22 EUGM | WEI | Moving Beyond the Comfort Zone in Practicing Translat...Cytel USA
1. The document discusses moving beyond conventional practices in translational statistics to obtain more robust and clinically meaningful results from clinical studies.
2. Several methodology issues are discussed, including how to define primary endpoints when there are multiple outcomes, how to handle dropouts and competing risks, and how to quantify treatment contrasts in a model-free way.
3. Alternative approaches are proposed for various types of studies, such as using restricted mean survival times instead of hazard ratios for survival analyses and performing meta-analyses for evaluating safety issues using large amounts of data.
This document discusses medical complexity and complications experienced by patients with traumatically induced disorders of consciousness. It begins with an overview and definitions of various disorders of consciousness including coma, vegetative state, and minimally conscious state. It then discusses outcomes from studies showing high rates of medical complications in these patients that can impact recovery. Several key points are made: 1) Patients with disorders of consciousness have high rates of rehospitalization, often for infections, seizures, or neurological issues; 2) They experience many medical complications like spasticity, dysautonomia, and pulmonary embolisms; 3) Active duty military with disorders of consciousness from combat injuries face even higher medical complexity. Proper assessment and medical stabilization is crucial for
Meditacion ayuda a la resitencia de enfermedades cerebralesRAUL TAYA PEREZ
This summary provides the key points from the document in 3 sentences:
The study investigated whether improvements in muscle strength and aerobic capacity (VO2peak) from progressive resistance training (PRT) mediated improvements in cognitive function for older adults with mild cognitive impairment. The results showed that PRT significantly improved upper body, lower body, and whole body strength more than a sham exercise control. Higher strength scores after PRT, but not changes in VO2peak, were significantly associated with improvements in cognition. Greater lower body strength gains partially mediated the effect of PRT on improving global cognition, but not executive function.
A Simulated Diabetes Learning Intervention Improves Provider Knowledge and Co...HMO Research Network
A simulated learning intervention using interactive virtual patient cases improved provider knowledge and confidence in managing diabetes compared to a control group. 341 resident physicians from 19 programs were randomized to an early intervention group that completed 12 virtual patient cases over 8 months or a late intervention control group. The early intervention group scored higher on a diabetes knowledge survey and reported greater confidence and knowledge in diabetes management topics compared to the control group. The results provide evidence that simulated learning can help transfer knowledge to improved care of real patients.
Kimberley Haines is a senior ICU physiotherapist and the Allied Health Research Lead at Western Health. Her academic research focusses on the long term progress of ICU survivors. Here she discusses the developing puzzle of ICU outcomes.
This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of rituximab for relapsing-remitting multiple sclerosis. 104 patients were randomized to receive either rituximab or placebo intravenous infusions. The primary outcome was the number of gadolinium-enhancing lesions on MRI scans from weeks 12-24. Patients receiving rituximab had significantly fewer lesions compared to placebo, indicating rituximab reduces disease activity in multiple sclerosis. Rituximab also decreased relapse rates and reduced lesion volumes on MRI. The most common adverse events were mild to moderate infusion reactions. This study provides evidence that B cell depletion with rituximab is effective and relatively safe for rel
Clinical prediction rules use combinations of clinical findings to predict the probability of a specific condition or outcome. This document summarizes several clinical prediction rules for orthopedic conditions seen in outpatient settings, including rules for ankle injuries, knee injuries, patellofemoral pain, hip osteoarthritis, and low back pain. It provides details on the clinical findings and validation levels for each rule. The document concludes by describing where to find more information on clinical prediction rules and validation studies.
1) The study examined the effects of Amantadine Hydrochloride (AH) on 184 patients with traumatic brain injury (TBI) and disorders of consciousness. Patients were randomly assigned to receive either AH or a placebo for 4 weeks.
2) After 4 weeks of treatment, patients receiving AH showed greater improvement on measures of disability (DRS) and consciousness (CRS-R) compared to those receiving the placebo. However, these treatment effects diminished after a 2-week washout period without AH.
3) The most common adverse effects were insomnia, agitation, and restlessness, with similar rates between the AH and placebo groups. The study provides preliminary evidence that AH may be effective for improving outcomes in
Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells. Two phase III trials, OPERA I and OPERA II, compared ocrelizumab to interferon beta-1a in patients with relapsing-remitting multiple sclerosis. The studies found that ocrelizumab significantly reduced annualized relapse rates, disability progression, and MRI activity compared to interferon beta-1a over 96 weeks with an acceptable safety profile. Ocrelizumab was generally well-tolerated with a higher rate of infusion-related reactions but lower rates of serious adverse events and infections compared to interferon beta-1a. The trials provide support for the role of B
Professor Andrew Davies is an Intensivist working at Peninsula Health in Melbourne. He has performed clinical research in the field of critical care for 20 years, as a participating investigator in over 50 studies (mostly clinical trials), predominantly in the areas of critical care nutrition, mechanical ventilation and acute lung injury and severe sepsis. He is a past Vice Chair of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS-CTG) with a special interest in nutrition in the ICU, and is a past Chair of the Australian and New Zealand Society of Parenteral and Enteral Nutrition (AuSPEN).
In this talk, Professor Davies tackles the often overlooked aspect of nutrition in the ICU and it’s potential benefits for our patients.
Switching therapy in Multiple sclerosisDivya Shilpa
1) A 37-year-old housewife, Mrs. S.D., has relapsing-remitting multiple sclerosis. She has experienced breakthrough disease activity while on interferon beta therapy.
2) The document discusses criteria for evaluating clinically relevant disease activity and considerations for treatment adjustment, including relapse rate, disability progression, and MRI findings. It also reviews options for switching or adding therapy, such as increasing interferon beta dose or switching to glatiramer acetate, natalizumab, fingolimod, or other drugs.
3) The evidence on switching therapies suggests that some patients with suboptimal response to interferon beta may experience reduced relapse rates and disability progression after switching to glat
This document discusses cognitive impairment in ICU patients. It notes that approximately 36% of mechanically ventilated patients and 25-54% of all ICU patients demonstrate cognitive impairment 6-12 months after discharge. The impairment affects executive function, memory, and mental processing. Risk factors include hypoxemia, hyperglycemia, delirium duration, hypotension, and sedative use. Delirium occurs in 74-80% of ICU patients and is associated with hypoperfusion in brain regions. Prevention strategies may include exercise in ICU to reduce delirium rates and cognitive rehabilitation. Maintaining good sleep and reducing delirium are important to mitigate cognitive impairment.
1) Both diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) require treatment, with the standard treatment for PDR being laser therapy. However, anti-VEGF therapy using ranibizumab is an alternative option supported by clinical evidence.
2) Several large randomized controlled trials found that ranibizumab treatment improved diabetic retinopathy severity scale (DRSS) scores and reduced the risk of DR progression and vision loss compared to laser therapy. Ranibizumab also led to better visual acuity outcomes in patients with and without DME.
3) Based on this evidence, the author prefers anti-VEGF therapy over laser therapy for their own PDR
This document discusses clinical prediction rules (CPRs), which are decision tools used by clinicians to predict outcomes. It covers the development, validation, and functions of CPRs. Specifically, it outlines 8 standards for developing a CPR, including clearly defining outcomes and predictors, ensuring reliability of predictors, having an adequate sample size, and accurately measuring a CPR's performance. An example CPR for ankle fractures is used to illustrate the development process. The document emphasizes the importance of prospectively validating CPRs in new populations before implementation, to assess their accuracy outside the initial study.
This document reviews treatments for neuroendocrine tumors (NETs), including peptide receptor radionuclide therapy (PRRT). It summarizes the evidence for various NET treatment options such as surgery, somatostatin analogs, PRRT, chemotherapy, and targeted therapies. It also provides an overview of a PRRT treatment day and integrates PRRT with other NET therapies. Clinical trial data is presented demonstrating the efficacy of PRRT and targeted therapies such as everolimus and sunitinib in extending progression-free survival for NETs. The conclusion emphasizes treating NETs only when necessary and considering surgery first followed by somatostatin analogs, PRRT, intra-arterial therapies,
This document provides an agenda and overview for the HSG 2016 conference. It summarizes the conference attendance numbers, recognizes sponsors and award recipients, and thanks outgoing and welcomes new board members. It highlights the HSG's strategic plan and 2016 accomplishments including clinical trials. Speakers discuss the future of HD care including education, coordinated care models, and improving access. The future of HD clinical trials is outlined including new recruitment strategies, quantitative disease models, virtual visits, objective measures, digital biomarkers from smartphones, and the need for new measurement classes.
This document provides information on diagnosing Huntington's disease (HD). It discusses the clinical features of HD including motor dysfunction such as chorea, cognitive impairment, and psychiatric features. The diagnostic evaluation for patients with a family history of HD or symptoms is described, including use of the Unified Huntington's Disease Rating Scale. Differential diagnoses for chorea are also reviewed, including other genetic, metabolic, autoimmune, and drug-induced causes. Workup of patients with chorea may include blood tests, imaging, and genetic testing.
- The study compared ocrelizumab (OCR) to placebo in treating primary progressive multiple sclerosis (PPMS) over approximately 3 years. Baseline characteristics were balanced between the treatment groups.
- OCR met the primary endpoint of reducing disability progression confirmed at 12 weeks compared to placebo. Key secondary endpoints including disability progression at 24 weeks, timed walking test, brain lesion volume, and brain volume loss were also significantly improved by OCR compared to placebo.
- Adverse events including infections were more common with OCR, but serious adverse events and discontinuation due to adverse events were similar between groups. Safety analyses are ongoing given a higher number of reported cancers with OCR, but differences must be considered in
Actrims 2016 opera poster hauser_p024 (1)BartsMSBlog
The document summarizes results from two Phase III clinical trials called OPERA I and OPERA II that compared the efficacy and safety of ocrelizumab (OCR) to interferon beta-1a (IFN β-1a) in patients with relapsing multiple sclerosis (RMS). Key results include:
1) OCR significantly reduced annualized relapse rates (ARR) by 46-47% compared to IFN β-1a in both studies. OCR also reduced disability progression and brain lesion activity to a greater extent than IFN β-1a.
2) A higher proportion of patients on OCR achieved no evidence of disease activity compared to those on IFN β-1a.
Safety and Efficacy of Low Dose versus Standard Dose of Alteplase for Stroke Thrombolysis in Hospital Sultanah Nur Zahirah (HSNZ)
Presentation Slides by Ms Mahfuzah Ishak, presented on the 14th National Conference for Clinical Research (NCCR) 2021 Dr Wu Lien Teh Youth Investigator Awards (YIA) on 19th August 2021
Following are the links for this presentation on Zenodo Repository:
Presentation Slides: https://zenodo.org/record/5348496
E-Poster: https://zenodo.org/record/5348723
Associated Factors of Stroke Severity Among Young Adult Stroke Patients in Malaysia from National Neurology Registry 2014 - 2018
Presentation Slides by Ms Fara Waheda Jusoh, presented on the 14th National Conference for Clinical Research (NCCR) 2021 Dr Wu Lien Teh Youth Investigator Awards (YIA) on 19th August 2021
Following are the links for this presentation on Zenodo Repository:
Presentation Slides: https://zenodo.org/record/5348488
E-Poster: https://zenodo.org/record/5348580
2014-10-22 EUGM | WEI | Moving Beyond the Comfort Zone in Practicing Translat...Cytel USA
1. The document discusses moving beyond conventional practices in translational statistics to obtain more robust and clinically meaningful results from clinical studies.
2. Several methodology issues are discussed, including how to define primary endpoints when there are multiple outcomes, how to handle dropouts and competing risks, and how to quantify treatment contrasts in a model-free way.
3. Alternative approaches are proposed for various types of studies, such as using restricted mean survival times instead of hazard ratios for survival analyses and performing meta-analyses for evaluating safety issues using large amounts of data.
This document discusses medical complexity and complications experienced by patients with traumatically induced disorders of consciousness. It begins with an overview and definitions of various disorders of consciousness including coma, vegetative state, and minimally conscious state. It then discusses outcomes from studies showing high rates of medical complications in these patients that can impact recovery. Several key points are made: 1) Patients with disorders of consciousness have high rates of rehospitalization, often for infections, seizures, or neurological issues; 2) They experience many medical complications like spasticity, dysautonomia, and pulmonary embolisms; 3) Active duty military with disorders of consciousness from combat injuries face even higher medical complexity. Proper assessment and medical stabilization is crucial for
Meditacion ayuda a la resitencia de enfermedades cerebralesRAUL TAYA PEREZ
This summary provides the key points from the document in 3 sentences:
The study investigated whether improvements in muscle strength and aerobic capacity (VO2peak) from progressive resistance training (PRT) mediated improvements in cognitive function for older adults with mild cognitive impairment. The results showed that PRT significantly improved upper body, lower body, and whole body strength more than a sham exercise control. Higher strength scores after PRT, but not changes in VO2peak, were significantly associated with improvements in cognition. Greater lower body strength gains partially mediated the effect of PRT on improving global cognition, but not executive function.
A Simulated Diabetes Learning Intervention Improves Provider Knowledge and Co...HMO Research Network
A simulated learning intervention using interactive virtual patient cases improved provider knowledge and confidence in managing diabetes compared to a control group. 341 resident physicians from 19 programs were randomized to an early intervention group that completed 12 virtual patient cases over 8 months or a late intervention control group. The early intervention group scored higher on a diabetes knowledge survey and reported greater confidence and knowledge in diabetes management topics compared to the control group. The results provide evidence that simulated learning can help transfer knowledge to improved care of real patients.
Kimberley Haines is a senior ICU physiotherapist and the Allied Health Research Lead at Western Health. Her academic research focusses on the long term progress of ICU survivors. Here she discusses the developing puzzle of ICU outcomes.
This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of rituximab for relapsing-remitting multiple sclerosis. 104 patients were randomized to receive either rituximab or placebo intravenous infusions. The primary outcome was the number of gadolinium-enhancing lesions on MRI scans from weeks 12-24. Patients receiving rituximab had significantly fewer lesions compared to placebo, indicating rituximab reduces disease activity in multiple sclerosis. Rituximab also decreased relapse rates and reduced lesion volumes on MRI. The most common adverse events were mild to moderate infusion reactions. This study provides evidence that B cell depletion with rituximab is effective and relatively safe for rel
Clinical prediction rules use combinations of clinical findings to predict the probability of a specific condition or outcome. This document summarizes several clinical prediction rules for orthopedic conditions seen in outpatient settings, including rules for ankle injuries, knee injuries, patellofemoral pain, hip osteoarthritis, and low back pain. It provides details on the clinical findings and validation levels for each rule. The document concludes by describing where to find more information on clinical prediction rules and validation studies.
1) The study examined the effects of Amantadine Hydrochloride (AH) on 184 patients with traumatic brain injury (TBI) and disorders of consciousness. Patients were randomly assigned to receive either AH or a placebo for 4 weeks.
2) After 4 weeks of treatment, patients receiving AH showed greater improvement on measures of disability (DRS) and consciousness (CRS-R) compared to those receiving the placebo. However, these treatment effects diminished after a 2-week washout period without AH.
3) The most common adverse effects were insomnia, agitation, and restlessness, with similar rates between the AH and placebo groups. The study provides preliminary evidence that AH may be effective for improving outcomes in
Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells. Two phase III trials, OPERA I and OPERA II, compared ocrelizumab to interferon beta-1a in patients with relapsing-remitting multiple sclerosis. The studies found that ocrelizumab significantly reduced annualized relapse rates, disability progression, and MRI activity compared to interferon beta-1a over 96 weeks with an acceptable safety profile. Ocrelizumab was generally well-tolerated with a higher rate of infusion-related reactions but lower rates of serious adverse events and infections compared to interferon beta-1a. The trials provide support for the role of B
Professor Andrew Davies is an Intensivist working at Peninsula Health in Melbourne. He has performed clinical research in the field of critical care for 20 years, as a participating investigator in over 50 studies (mostly clinical trials), predominantly in the areas of critical care nutrition, mechanical ventilation and acute lung injury and severe sepsis. He is a past Vice Chair of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS-CTG) with a special interest in nutrition in the ICU, and is a past Chair of the Australian and New Zealand Society of Parenteral and Enteral Nutrition (AuSPEN).
In this talk, Professor Davies tackles the often overlooked aspect of nutrition in the ICU and it’s potential benefits for our patients.
Switching therapy in Multiple sclerosisDivya Shilpa
1) A 37-year-old housewife, Mrs. S.D., has relapsing-remitting multiple sclerosis. She has experienced breakthrough disease activity while on interferon beta therapy.
2) The document discusses criteria for evaluating clinically relevant disease activity and considerations for treatment adjustment, including relapse rate, disability progression, and MRI findings. It also reviews options for switching or adding therapy, such as increasing interferon beta dose or switching to glatiramer acetate, natalizumab, fingolimod, or other drugs.
3) The evidence on switching therapies suggests that some patients with suboptimal response to interferon beta may experience reduced relapse rates and disability progression after switching to glat
This document discusses cognitive impairment in ICU patients. It notes that approximately 36% of mechanically ventilated patients and 25-54% of all ICU patients demonstrate cognitive impairment 6-12 months after discharge. The impairment affects executive function, memory, and mental processing. Risk factors include hypoxemia, hyperglycemia, delirium duration, hypotension, and sedative use. Delirium occurs in 74-80% of ICU patients and is associated with hypoperfusion in brain regions. Prevention strategies may include exercise in ICU to reduce delirium rates and cognitive rehabilitation. Maintaining good sleep and reducing delirium are important to mitigate cognitive impairment.
1) Both diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) require treatment, with the standard treatment for PDR being laser therapy. However, anti-VEGF therapy using ranibizumab is an alternative option supported by clinical evidence.
2) Several large randomized controlled trials found that ranibizumab treatment improved diabetic retinopathy severity scale (DRSS) scores and reduced the risk of DR progression and vision loss compared to laser therapy. Ranibizumab also led to better visual acuity outcomes in patients with and without DME.
3) Based on this evidence, the author prefers anti-VEGF therapy over laser therapy for their own PDR
This document discusses clinical prediction rules (CPRs), which are decision tools used by clinicians to predict outcomes. It covers the development, validation, and functions of CPRs. Specifically, it outlines 8 standards for developing a CPR, including clearly defining outcomes and predictors, ensuring reliability of predictors, having an adequate sample size, and accurately measuring a CPR's performance. An example CPR for ankle fractures is used to illustrate the development process. The document emphasizes the importance of prospectively validating CPRs in new populations before implementation, to assess their accuracy outside the initial study.
This document reviews treatments for neuroendocrine tumors (NETs), including peptide receptor radionuclide therapy (PRRT). It summarizes the evidence for various NET treatment options such as surgery, somatostatin analogs, PRRT, chemotherapy, and targeted therapies. It also provides an overview of a PRRT treatment day and integrates PRRT with other NET therapies. Clinical trial data is presented demonstrating the efficacy of PRRT and targeted therapies such as everolimus and sunitinib in extending progression-free survival for NETs. The conclusion emphasizes treating NETs only when necessary and considering surgery first followed by somatostatin analogs, PRRT, intra-arterial therapies,
This document provides an agenda and overview for the HSG 2016 conference. It summarizes the conference attendance numbers, recognizes sponsors and award recipients, and thanks outgoing and welcomes new board members. It highlights the HSG's strategic plan and 2016 accomplishments including clinical trials. Speakers discuss the future of HD care including education, coordinated care models, and improving access. The future of HD clinical trials is outlined including new recruitment strategies, quantitative disease models, virtual visits, objective measures, digital biomarkers from smartphones, and the need for new measurement classes.
Gene therapy advanced treatments for a new era aranca special reportAranca
Aranca's Report on Gene Therapy - a promising tool for Cancer, Parkinson's, HIV, severe combined immuno-deficiencies, hemophilia etc. In this report, you will discover the challenges associated with Gene Therapy as well as its expected future.
The strategic plan outlines the Huntington Study Group's (HSG) vision, mission, and values, as well as strategic initiatives from 2015-2019 to investigate new HD therapies, expand the therapy pipeline, educate about HD research and care, develop sensitive outcome measures, expand the HSG research network, improve clinical trial efficiency, identify and develop new investigators, build human capital within HSG, and foster community. Key actions include completing clinical trials, launching new trials annually, developing online training and tools, adding new sites, and recognizing members' contributions.
- The addition of selective internal radiation therapy (SIRT) to sorafenib (SOR) did not significantly improve overall survival compared to SOR alone in patients with advanced hepatocellular carcinoma based on two randomized controlled trials.
- Subgroup analyses found potential clinical benefits for younger patients, those with non-alcoholic disease etiology, and those without cirrhosis.
- Regorafenib, a multi-kinase inhibitor, significantly improved progression-free survival, overall survival, and disease control compared to placebo in patients with hepatocellular carcinoma progressing on sorafenib.
- Lenvatinib, an oral multi-kinase inhibitor, demonstrated non-inferior
Citalopram enhances action inhibition systems in Parkinson’s diseaseZheng Ye
1) The study investigated whether the selective serotonin reuptake inhibitor (SSRI) citalopram could reduce impulsivity and enhance response inhibition systems in patients with Parkinson's disease (PD).
2) The results showed that PD impaired both action restraint and cancellation compared to healthy controls. Citalopram improved behavioral performance on inhibition tasks in PD patients depending on disease severity.
3) Citalopram enhanced activation in the right inferior frontal gyrus, a brain region involved in response inhibition. The degree of enhancement correlated with reductions in impulsivity, supporting the role of serotonin in regulating inhibitory control.
Presentation on study to assess longitudinal changes in cognitive function among individuals with pediatric MS evaluated within the US Network of Pediatric MS Centers.
Efficacy and safety of microvascular decompression for trigeminal in patients...neurologia segura
This study evaluated the efficacy and safety of microvascular decompression (MVD) for treating trigeminal neuralgia in patients with morbid obesity. The study found that while MVD surgery took longer and had higher risks in obese patients, it was still effective at reducing pain. Specifically, obese patients had longer surgery/anesthesia times, more pre-existing health issues, and higher complication rates during intubation. However, obese patients still experienced significant pain relief following surgery similar to non-obese patients, with over 65% reporting an excellent outcome. The study concluded that MVD should be considered for obese patients with TN when it is the only effective treatment option, and can be performed safely in specialized medical centers.
- The document discusses various factors that may predict response and survival outcomes for men with metastatic prostate cancer receiving androgen deprivation therapy (ADT).
- Several studies have found that higher tumor levels of dihydrotestosterone (DHT) and androgen receptor content predicted better responses to ADT.
- Inherited genetic variants in hormone-related genes and the presence of certain gene fusions have also been linked to response to ADT.
- Lower PSA levels after 7 months of ADT induction, such as less than 0.2 ng/mL, are associated with longer survival. Bone pain, higher Gleason score, and other factors also predict poorer survival.
This document discusses several topics related to predicting response to hormonal therapy and survival in men with metastatic prostate cancer:
1) Androgen deprivation therapy (ADT) is standard treatment but not all patients respond equally well. Factors like surgical vs medical ADT and combined vs monotherapy have been studied.
2) Higher tumor levels of dihydrotestosterone (DHT) and androgen receptor content in tumors have been associated with better response to ADT and longer survival times.
3) Inherited genetic variants in hormone-related genes may also play a role in response to ADT, though more research is needed. The presence of certain gene fusions also appears to impact response.
4)
This document summarizes the findings of the REDOXS study, a randomized controlled trial that investigated the effects of high-dose glutamine and antioxidant supplementation in critically ill patients with multi-organ failure. The study found that glutamine supplementation was not beneficial and may have been harmful, increasing mortality. Subgroup analyses found the highest risk of harm with glutamine in patients who had renal dysfunction at enrollment. An updated meta-analysis of intravenous glutamine trials did not find an overall increase in mortality, though the REDOXS study results suggest glutamine could be harmful in certain critically ill populations such as those with renal failure.
The document provides an overview of a presentation on new agents and evolving strategies for castration-sensitive prostate cancer. It includes 3 key points:
1) Several phase 3 trials have shown that the addition of docetaxel or novel hormone therapies like abiraterone or enzalutamide to androgen deprivation therapy improves outcomes for men with metastatic castration-sensitive prostate cancer.
2) For men with low-volume disease, androgen deprivation therapy alone may be sufficient, while those with high-volume disease seem to benefit most from early chemotherapy.
3) Ongoing trials are evaluating the potential benefits of "triplet" combinations of androgen deprivation therapy, chemotherapy, and novel
This document summarizes a presentation on tackling prostate cancer and improving treatment outcomes. It discusses that prostate cancer incidence is increasing due to aging and screening. Prostate cancer is the second most common cancer in men and is an androgenic disease related to testosterone and the androgen receptor. The presentation reviews prostate cancer risk stratification and how docetaxel added to androgen deprivation therapy can improve outcomes for metastatic hormone-sensitive prostate cancer based on clinical trial results. It also discusses therapies such as abiraterone that have shown survival benefits for castrate-resistant prostate cancer based on additional clinical trials.
This study examined the effects of deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) on balance and gait in people with Parkinson's disease. Quantitative measurements were taken before and after surgery using inertial sensors. Results showed that GPi stimulation led to greater improvements than STN stimulation in several gait and balance metrics like stride length and turning speed. Both sites worsened arm movement. Inertial sensors were useful for precisely measuring changes over time to understand how DBS affects balance and mobility.
This document summarizes preliminary results from a study of 267 prostate cancer patients treated with high-dose intensity-modulated radiation therapy (IMRT) guided by seed markers and kV X-ray imaging. Toxicity outcomes were excellent, with only 5 patients experiencing rectal complaints and 1 developing urinary incontinence. Biochemical disease-free survival was 97% at a median follow-up of 1.5 years. Potency preservation rates were high, with 77% of initially potent non-hormonally treated patients maintaining some function. The results suggest modern image-guided IMRT may achieve low morbidity for prostate cancer treatment.
Delirium in critically ill patients bogota043009hospira2010
The document discusses acute brain dysfunction, specifically delirium, in critically ill patients. Some key points:
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- Sedatives like benzodiazepines and opioids are risk factors for delirium. Protocols aiming to reduce exposure can help prevent delirium.
- Studies found the alpha-2 agonist dexmedetomidine reduced delirium and cognitive dysfunction compared to lorazepam. Antipsychotics may help
This randomized controlled trial evaluated the safety and efficacy of renal denervation for treatment-resistant hypertension. 535 patients with uncontrolled hypertension despite receiving 3 or more antihypertensive medications were randomized to renal denervation or a sham procedure. The primary outcome was the difference in office systolic blood pressure reduction between groups at 6 months, with a non-inferiority margin of 5 mmHg. Renal denervation did not meet the primary endpoint, with a between-group difference of -2.39 mmHg (p=0.26). It also did not meet the powered secondary endpoint of 24-hour ambulatory blood pressure change with a margin of 2 mmHg. Major adverse event rates were similar between groups
Clinical Impact of New HIV Data From the 2016 Comorbidities-Adverse Drug Reac...hivlifeinfo
In this downloadable slideset, expert faculty members Todd T. Brown, MD, PhD, and Jordan E. Lake, MD, MSc, review key studies presented at the 2016 Comorbidities/Adverse Drug Reactions Workshop.
Format: Microsoft PowerPoint (.ppt)
File size: 1.37 MB
Date posted: 10/14/2016
- The study compared 412 patients with spontaneous coronary artery dissection (SCAD) who participated in cardiac rehabilitation (CR) versus those who did not.
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A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
share - Lions, tigers, AI and health misinformation, oh my!.pptxTina Purnat
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Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
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There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
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Histololgy of Female Reproductive System.pptxAyeshaZaid1
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In some case, your chronic prostatitis may be related to over-masturbation. Generally, natural medicine Diuretic and Anti-inflammatory Pill can help mee get a cure.
2. Most Influential Insights
HSG 2016: DISCOVERING OUR FUTURE
In imaging and biomarkers…
Altered PDE10A expression detectable early
before symptomatic onset in HD
Presented by: Flavia Niccolini, PhD
In the clinic…
Identification of genetic factors that modify
clinical onset of Huntington’s disease
Presented by: Jong-Min Lee, PhD
3. Institute of Psychiatry, Psychology and
Neuroscience (IoPPN)
Department of Basic and Clinical Neuroscience
ALTERED PDE10A EXPRESSION DETECTABLE
EARLY BEFORE SYMPTOMATIC ONSET IN
HUNTINGTON’S DISEASE
Niccolini F, Haider S, Reis Marques T, Muhlert N, Tziortzi AC,
Searle GE, Natesan S, Piccini P, Kapur S, Rabiner EA,
Gunn RN, Tabrizi SJ and Politis M
Neurodegeneration Imaging Group
www.nig-politis.com
5. PDE10A & HDwww.nig-politis.com
o Preclinical research in transgenic HD animal models suggests a direct
effect of mutant huntingtin on PDE-10A expression via the alteration of
transcription, synthesis and trafficking
Hu et al., 2004; Leuti et al., 2013
Leuti et al., 2013 Hebb et al., 2004
7. AIMwww.nig-politis.com
To study a unique cohort of Early Premanifest HD gene
expansion carriers (HDGECs) and investigate the
expression of PDE10A enzyme using [11C]IMA107 PET
molecular imaging
Participants
o 12 early premanifest HDGECs who were the furthest from
the predicted disease onset
o 12 aged and sex-matched healthy controls
8. Study procedures - 1
Motor:
UHDRS TMS
Cognitive:
CANTAB® :
o Psychomotor speed: RTI
o Episodic memory: PAL &
PRM
o Working memory &
executive function: OTS
o Language processing: GNT
Neuropsychiatric :
• PBA-S
• BDI-II
• HDRS
Clinical assessments:
Functional capacity:
• UHDRS-TFC
• UHDRS-IS
• UHDRS-FAS
• SF-36
www.nig-politis.com
9. Study procedures - 2
Imaging assessments:
• One [11C]IMA107 PET scan (no arterial metabolites, 90 min)
• One 3-T MRI scan (T1-weighted; FGATIR; FLAWS; DTI 32 Dir BLIPUP &
BLIPDOWN)
PET analysis
• Frame-by-frame realignment for movement correction
• SRTM – cerebellum reference, coreg, BPND
MRI analysis
• FreeSurfer’s image analysis suite (version 5.3.0 )
• VBM morphometry SPM8 software package
www.nig-politis.com
Mansur et al., 2016
10. www.nig-politis.com
Clinical characteristics
Healthy controls Premanifest HDGECs
No (Sex) 12 (8M/4F) 12 (7M/5F)
Age (years ± SD) 40.0 (±6.2) 41.1 (±7.5)
CAGr (± SD) [range] - 41.8 (±1.3) [40-44]
DBS1
(± SD) [range] - 254.4 (± 46.8) [153-323]
90% p to onset2
(years
±SD) [range]
- 25 (±6.9) [17-43]
UHDRS TMS (±SD) 0 (±0) 0 (±0)
UHDRS DCL (±SD) - 0 (±0)
1Disease burden score: age x (CAG length–35.5); 290% p to onset: Paulsen et al., 2008
16. PDE10A PET analysiswww.nig-politis.com
LAYER 1: [11C]IMA-107 BPND based on anatomically defined
ROIs
LAYER 2: [11C]IMA-107 BPND based on connectivity-based
parcellations of ROIs (limbic, cognitive and sensorimotor
striatum) according to cortical-striatal connectivity profiles
LAYER 3: [11C]IMA-107 BPND based on connectivity-based
parcellations of ROIs (striatonigral/striatopallidal internal and
striatopallidal external projecting segments of striatum) based
on striatal connections with GPe and SN/GPi
17. [11C]IMA107 BPND based on anatomy
www.nig-politis.com
% changes
Caudate −33.0%
Putamen −30.5%
Ventral striatum −16.9%
Pallidum −25.6%
Motor Thal Nuclei +34.5%
Sub Nigra +9.0%
23. PDE10A in manifest HDGECswww.nig-politis.com
5 Manifest HDGECs (HD1-4)
UHDRS-TMS = 37
DBS = 426
[18F]JNJ42259152
Ahmad et al., 2014
-63%
-71%
24. PDE10A in HDGECs
www.nig-politis.com
8 Early Manifest HDGECs
(HD1-2)
3 Premanifest HDGECs
(mean of 12 years from
predicted onset)
[18F]MNI-659
Russell et al., 2014
25. PDE10A changes in HDGECs
www.nig-politis.com
Russell et al., 2016
6 manifest and 2 premanifest
HDGECs
[18F]MNI-659
PDE10A mean annualized
rates of decline
−5.8% −6.9%
−16.6
26. Conclusions
o Bidirectional changes in PDE10A expression in premanifest
HDGECs, which are associated with the risk of symptomatic
conversion, and are detectable up to a mean of 25 years
before the predicted onset of clinical symptoms
o PDE-10A expression could be a biomarker of striatal MSNs
integrity and [11C]IMA107 PET may be a useful tool for future
trials of disease-modifying therapeutics aiming to delay the
onset and slow the progression of HD
www.nig-politis.com
27. Neurodegeneration Imaging Group
Marios Politis
Heather Wilson
Tayyabah Yousaf
Gennaro Pagano
George Dervenoulas
Konstantinos Diamantopoulos
Sotirios Polychronis
Juan Bonfante
www.nig-politis.com
KCL NIHR BRC
28. Inclusion/Exclusion Criteriawww.nig-politis.com
Inclusion:
12 Early Premanifest HDGECs:
• Age 21–75 years
• Capable of giving informed consent
• HD gene carriers with ≥ 40 CAG repeats
• UHDRS TMS of 0 indicating lack of motor signs with UHDRS DCL = 0
12 Healthy Controls:
• Ability to give informed consent
• No history of any psychiatric or neurological diseases
Exclusion:
• No medications with known action on PDE10A
• Presence of psychiatric and/or other neurological disorders
• Standard for PET and MRI scanning (e.g. pregnancy, cancer, etc)
• Standard for the ligand (e.g. coffee, tea, papaverine etc)
The Huntington Study Group, 1996
29. CANTAB tests
Psychomotor Speed
RTI – simple & 5-choice
Language Processing
GNT
Working memory &
Executive Function
OTS
www.nig-politis.com
Episodic Memory
PAL PRM
31. Genetic modifiers of HD
Jong-Min Lee, Ph.D. Assistant Professor
on behalf of the GeM-HD Consortium
Center for Human Genetic Research, Massachusetts General Hospital
Department of Neurology, Harvard Medical School
32. Genetically supported targets can double the success rates of clinical trials
Nature Genetics, 2015, 47, 856
Cell, 1993, 72, 971
Cell, 2015, 162, 516
33. Cell, 1993, 72, 971
Discovery of the cause of HD
Autosomal dominant
HD
Normal
34. The cause of HD was described in 1993 paper
Duff beer is HTT CAG expansion mutation
Beer belly caused by drinking beer is HD
36. CRISPR strategy for perfect allele specificity
PAM-altering SNPs
PromotorNCG NGT
gRNA 1 gRNA 2
Normal
chromosome
Normal
CAG
Transcription
start
Promotor NGGNGG
gRNA 1 gRNA 2
Expanded
CAG
Mutant
chromosome
PAM-altering SNP PAM-altering SNP
Large deletion
37. Permanent inactivation of mutant allele by CRISPR
B. CAG region in DNA
Mutant
Normal
GM01169 TSCC 1
Normal
Mutant
GM01169 TSCC 1
C. CAG region in RNA
D. Total HTT protein
Mutant
GM01169 TSCC 1
Total
GM01169 TSCC 1
E. Mutant HTT protein
A. Targeted DNA
~700 bp
GM01169 TSCC 1
F. ACTB protein
GM01169 TSCC 1
~44kb deletion
Normal
Mutant
Normal HTT RNA
Mutant HTT RNAx
38. Nature Reviews Genetics Nature Reviews Neurology
Human Molecular Genetics
Outcomes of 1993 cloning paper: CRISPR treatment strategy
40. Genetic modifiers of HD
Comparing two groups of beer lovers
Duff beer is HTT CAG expansion mutation
Beer belly caused by drinking beer is HD
TV time is a genetic modifier
41. Age at onset is determined by HTT CAG repeat length and modifiers
43. Steps to identify HD genetic modifiers by GWA
2.Genotyping3.Associationanalysis
(examples)
Genome-wide SNP genotyping and genotype imputation
CAG
Ageatonset(AO)
DistancetoexpectedAO
(Residual)
1.Phenotyping
CAG
DistancetoexpectedAO
(residual)
ExpectedAO
Residual
0 1 2
SNP minor allele count
Continuous analysis
Genotype A Genotype C
Phenotype:
Early
200 80
Phenotype:
Late
200 120
Dichotomous analysis
44. Significance Identification of genetic modifiers of HD through GWA: CAG 40-55
Suggestive significance (p-value < 0.00001)
3 genome-wide significant signals and numerous suggestive loci
Genome-wide significance (p-value < 0.00000005)
45. 2 independent genome-wide significant modifier signals at Chr15ConditionalanalysisSingleSNPanalysis
Effect of green SNP was removed
Effect of red SNP was removed
46. Genome-wide significant modifier signals at Chr8ConditionalanalysisSingleSNPanalysis
Effect of red SNP was removed
Effect of red SNP was removed
47. 0 2 4 6 8
R-squared (%)
0 0.1 0.2 0.3
Frequency of significance
(density)
FrequencyofR-squared
(density)
Significance(-log10(p-value))
Grey, top SNP
Orange, SNPs p < 0.00001
Blue, SNPs p < 0.0001
Green, SNPs p < 0.001
Red, SNPs p < 0.01
Purple, SNPs p < 0.05
010203040506000.511.52
0 2 4 6 8
More to find in the genome
48. HD modifier GWA results (GeM MOA) are available at HDinHD.org
Journal of Huntington’s Disease
49. Identified mother nature’s experiments that resulted in modification of age at onset
Genome-wide significant loci: chromosome 15 and 8
Numerous suggestive loci were also discovered
The causal modifier variation / gene is not yet unequivocally known
Pathway analysis implicated DNA maintenance and mitochondria-related pathways
Follow-up genetic analysis and molecular experiments are on going
Genetics increases success rate of clinical trials
Identification of the cause of HD made gene targeting approaches possible
Discovery of genetic modifiers may contribute to the development of disease-delaying treatments
Summary
50. Michael Chao
Kawther Abu Elneel
Tammy Gillis
Diane Lucente
Jayalakshmi Mysore
Marisa Ramos
Denise Harold, Cardiff
Peter Holmans, Cardiff
Lesley Jones, Cardiff
Seung Kwak, CHDI
Richard Myers, BU
Michael Orth, Ulm
Vanessa Wheeler, CHGR, MGH
Marcy MacDonald, CHGR, MGH
James Gusella, CHGR, MGH
Samples and data
Huntington Study Group
HD-MAPS Collaboration
PREDICT-HD Study of the HSG
REGISTRY Study of the EHDN
MIGEN Consortium for control
data
Acknowledgements
Funding
GeM-HD Consortium
51. Authors from HSG
HSG’s contribution to genetic study will lead to:
more samples, more phenotypes
more discoveries
being more successful in HD clinical trials
Editor's Notes
PDE10A is a dual substrate enzyme highly expressed in the striatal medium spiny neurons
PDE-10A regulates cAMP and cGMP downstream signaling cascades (e.g. cAMP/PKA/DARPP-32) that control the phosphorylation state and activity of several physiological effectors including gene transcription factors such as CREB, and various neurotransmitter receptors and voltage-gated ion channels
Previous work explored PDE-10A expression in transgenic Huntington’s disease mice, showing decreased PDE-10A protein and mRNA levels in the striatum
In humans, decreased PDE-10A levels were found in post-mortem striatal tissue
Moreover, PDE-10A inhibition with TP-10 was able to reduce the loss of striatal and cortical neurons, to increase striatal and cortical CREB phosphorylation, and to delay the development of neurological deficits in HD animal models
Motor function was assessed with the UHDRS TMS. Functional capacity was assessed with clinician-based [Total Functional Capacity Scale (TFC), Independence Scale (IS), UHDRS functional assessment] and participant self-reported [36-Item Short Form Health Survey (SF-36) functional and quality-of-life measures and assessments. Neuropsychiatric symptoms were assessed
with the shortened form of the problem behavior assessment (PBA, the Beck Depression Inventory-II (BDI-II), and the Hamilton Depression Rating Scale (HDRS).
Cognitive assessments were carried out using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and included assessments related to psychomotor speed (Reaction Time) episodic memory (Paired Associate Learning & Pattern Recognition Memory), executive function (One Touch Stockings of Cambridge) and language processing (Graded Naming Test).
MRI included a T1-weighted for co-registration with the PET images and for morphometric analysis; fast grey matter (GM) T1 inversion recovery (FGATIR ) and fluid and white matter (WM) suppression (FLAWS ) for improving delineation of subcortical brain regions
Diffusion-weighted data were acquired for performing a two-layered probabilistic tractography and connectivity-based functional parcellation of the striatum
We tested correction for movement using a frame-by-frame realignment procedure
Parametric images of 11C-IMA107 non-displaceable binding potential (BPND) were generated from the dynamic 11CIMA107 scans using a basis function implementation of the simplified reference tissue model, with the cerebellum as the
reference tissue for non-specific binding using an in-house software (c-wave) implemented in Matlab 8.2
As grey and white matter volumetric brain changes have been reported as one of the earliest changes in the course of HD, we wanted to explore whether this was also true for the earlier cohort of premanifest HDGECS studied here. We applied both voxel-based morphometry and volumetric analysis with Freesurfer.
predicted years to HD symptoms onset (90% probability) calculated on the basis of the variant of the survival analysis formula described by Langbehn (Paulsen et al., 2008)
All subjects underwent a battery of clinical assessments, which showed no deficits in motor and functional (P>0.10), neuropsychiatric (P>0.10), and cognitive (P>0.10) performance in early premanifest Huntington’s disease gene carriers compared to healthy controls
Neuropsychiatric assessments showed small non-significant differences between healthy controls and premanifest HDGECs, however the neuropsychiatric burden in our cohort of early premanifest HDGECs was minimal.
We found no volume changes at a voxel level in any brain regions, and Freesurfer subcortical and ventricle volumetric measures did not show significant differences between healthy controls and early premanifest HDGECs
we assessed the expression of PDE-10A enzyme in vivo with [11C]IMA107 PET, which is a specific and highly potent PDE-10A selective PET radioligand for human use. We performed a three-layered analysis of the [11C]IMA107 PET BPND in: (a) MR-based anatomically defined ROIs (caudate, putamen, ventral striatum, globus pallidus, substantia nigra and motor thalamic nuclei); (b) connectivity-based parcellations of ROIs (limbic, cognitive and sensorimotor striatum) according to cortical-striatal connectivity profiles; (c) connectivity-based parcellations of ROIs (striatonigral/striatopallidal internal and striatopallidal external projecting segments of striatum) based on striatal connections with globus pallidus externus and substantia nigra/globus pallidus internus, and so reflect the major parts of the indirect and direct pathways, respectively.
We found that [11C]IMA107 BPND was decreased in caudate (-33%), putamen (-30.5%) and globus pallidus (-25.6%), and increased in motor thalamic nuclei (+34.5%), with no significant changes observed in substantia nigra (+9%) and ventral striatum (-16.9%) in early premanifest HDGECs compared to healthy controls
Mean [11C]IMA107 BPND parametric images derived from 12 healthy controls (top) and 12 early premanifest HD gene carriers (bottom) in stereotaxic space overlaid onto the T1 weighted MNI template showing significant loss of striatal PDE-10A signal in the early premanifest HD gene carriers. Color bar reflects range of [11C]IMA107 BPND intensity
Individual [11C]IMA107 BPND analysis showed that 10 out of 12 early premanifest HDGECs (83.3%) had abnormally reduced striatal and abnormally increased motor thalamic nuclei [11C]IMA107 BPND values
Coronal summed [11C]IMA107 PET images co-registered and fused with 3-T MRI images for the thalamus of a 33-year-old healthy male showing normal thalamus [11C]IMA107 binding (BPND = 0.43) (left); a 38-year-old male premanifest Huntington’s disease gene carrier (CAGr: 44; DBS: 323; 17 years from predicted onset) showing high increases in thalamic [11C]IMA107 binding (BPND = 0.93) (middle-left); a 35-year-old male premanifest Huntington’s disease gene carrier (CAGr: 40; DBS: 153; 43 years from predicted onset) showing moderate increases in thalamic [11C]IMA107 binding (BPND = 0.64) (middle-right); and a 37-year-old male premanifest Huntington’s disease gene carrier (CAGr: 43; DBS: 277.5; 22 years from predicted onset) showing mild to moderate increases in thalamic [11C]IMA107 binding (BPND = 0.58) (right). Color bar reflects range of [11C]IMA107 BPND intensity.
We calculated [11C]IMA107 BPND in functional striatal subdivisions following probabilistic tractography and connectivity-based functional striatal parcellation
Cortico-striatal connectivity-based functional analysis 34% decreases in sensorimotor striatum but not limbic or cognitive in early premanifest HDGECs compared to healthy controls
Hence, we used the sensorimotor striatum as a seed mask since it was the only subdivision with significant PDE-10A decreases, to perform striatonigral and striatopallidal connectivity-based functional analysis
We found 33-34% [11C]IMA107 BPND decreases in striatonigral/striatopallidal internal and striatopallidal external projecting sensorimotor striatal segments
We found correlations between: (a) higher motor-thalamic-nuclei/striatal [11C]IMA107 BPND ratio and higher two (r=0.59; P=0.044) and five (r=0.59; P=0.043) year probability for symptomatic conversion; (b) higher motor-thalamic-nuclei/sensorimotor [11C]IMA107 BPND ratio and higher two (r=0.66; P=0.020), five (r=0.66; P=0.019) and 10 (r=0.63; P=0.027) year probability for symptomatic conversion and; (c) higher motor-thalamic-nuclei/striatopallidal [11C]IMA107 BPND ratio and higher two (r=0.85; P=0.001), five (r=0.82; P=0.001), 10 (r=0.76; P=0.004) and 15 (r=0.65; P=0.023) year probability for symptomatic conversion
Previous studies using similar samples have reported correlations at a 0.05 α level between decreased D2-receptors (van Oostrom et al., 2009) and increased activated microglia (Politis et al., 2011) in the striatum, and predicted 5-year probability of Huntington’s HD between decreased PDE-10A in striatopallidal projections and increased PDE-10A in motor thalamic nuclei correlated with the risk for symptomatic conversion up to a 0.001 α level with power to associate with predicted onset up to 15 years. To our knowledge, this is the strongest reported correlation with the risk of symptomatic HD conversion
A pilot PDE-10A PET study reported 60-70% decreases in striatal PDE-10A expression of five manifest Huntington’s disease patients with significant striatal atrophy
Using PET with [18F]MNI-659, Russell and colleagues (2014) have found 47.6% decreases in striatal and pallidal PDE-10A expression in eight early manifest Huntington’s disease patients and lower striatal [18F]MNI-659 binding was associated with disease severity and disease burden of pathology. Three premanifest Huntington’s disease gene carriers, who were a mean of 12 years from predicted onset, displayed decreases in striatal PDE-10A expression with a lesser degree compared to the group of manifest Huntington’s disease patients
The mean annualized rates of decline in signal in the caudate, putamen, and globus pallidus and the putamen were 16.6%, 6.9%, and 5.8%, respectively. In HC, the annualized reduction in signal in striatal regions was less than 1%. Longitudinal data in this small cohort of participants with early HD support [18F]MNI-659 PET imaging of PDE10 as a useful biomarker to track HD disease progression
All early premanifest HDGECs were asymptomatic based on the standardized total motor score (TMS) subscale (TMS = 0) of the Unified Huntington Disease Rating Scale (UHDRS) with a diagnostic confidence level of 0 (The Huntington Study Group, 1996).
We recruited 12 healthy individuals, matched for age and gender
All participants screened successfully to undertake PET and MRI scanning under standard criteria, had no history of other neurological or psychiatric disorders, and were not under treatment with substances with known actions in PDEs (e.g. apremilast, cilomilast, luteolin, piclamilast, roflumilast and ibudilast).
RTI=it provides measure of motor and mental response speeds, as well as measures of movement time and reaction time. The task is divided into five stages and the participant must react as soon as a yellow dot appears. PAL= Boxes are displayed on the screen and are opened in a randomized order. One or more of them will contain a pattern. The patterns are then displayed in the middle of the screen, and the participant must touch the box where the pattern was originally located. PRM is a test of visual pattern recognition memory in a 2-choice forced discrimination paradigm. Subject is presented with series visual patterns, one at a time, in the center of the screen. OTS assesses executive function, spatial planning and working memory and is based on the Tower of Hanoi test. OTS is a variant of the Stockings of Cambridge test and places greater demands on working memory as the subject has to visualize the solution. GNT assesses object-naming ability, but is in addition graded in difficulty to allow for individual differences.
In early premanifest Huntington’s disease gene carriers PDE-10A levels are decreased in the striatonigral (direct) and striatopallidal (indirect) neurons potentiating dopamine D1 and D2 receptors signaling and leading to disinhibition of motor thalamic nuclei. Increased PDE-10A levels in the motor thalamic nuclei may counterbalance the decreased inhibitory signals incoming from globus pallidus and substantia nigra and consequently, physiologically stimulate the cortex.
In manifest Huntington’s disease, ongoing and significant degeneration of striatopallidal projecting neurons and further PDE-10A decreases would lead to an even more unbalanced striatonigral/striatopallidal signaling. Motor-thalamic-nuclei compensatory mechanisms could gradually fail leading to an overflow of glutamate activity to the cortex, which will result in expression of Huntington’s disease symptoms.