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The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA, and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson's disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1741 participants had SAA data and of these 1030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD, and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively. We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary., (© 2024. The Author(s).)

The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson's disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1,741 participants had SAA data and of these 1,030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD, and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively. We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary., Competing Interests: COMPETING INTERESTS TD declares former employment for and employee stock options in Biogen. GP declares employment for F. Hoffmann-La Roche Ltd. and stock ownership for F. Hoffmann-La Roche Ltd., Atea, Novartis and Eli Lilly. MB declares travel grants from The Michael J. Fox Foundation. CG declares employment for The Michael J. Fox Foundation. KP declares consultancies for Curasen; was on a scientific advisory board for Curasen and Amprion; honoraria from invited scientific presentations to universities and professional societies not exceeding $5000 per year from California Congress of Clinical Neurology, California Neurological Society, and Johns Hopkins University; and patents or patent applications numbers 17/314,979 and 63/377,293. KP also declares grants to her institution (Stanford University School of Medicine) from NIH/NINDS NS115114, NS062684, NS075097, NIH/NIA U19 AG065156, P30 AG066515, The Michael J. Fox Foundation, Lewy Body Dementia Association, Alzheimer’s Drug Discovery Foundation, Sue Berghoff LBD Research Fellowship and the Knight Initiative for Brain Resilience. DW declares salary support from The Michael J. Fox Foundation for serving on an Executive Steering Committee for the PPMI and consultancies for Roche Pharma. DW declares membership on the npj Parkinson’s Disease Editorial Board. LC declares grants to her institution from Biogen (clinical trial funding), MJFF, UPMC Competitive Medical Research Fund, National Institutes of Health, and University of Pittsburgh; grant and travel support from MJFF; royalties from Wolters Kluwel (for authorship); and in-kind donation by Advanced Brain Monitoring of equipment for research study to her institution. CC declares grants from The Michael J. Fox Foundation and NIH/NINDS. CT declares consultancies for CNS Ratings, Australian Parkinson’s Mission, Biogen, Evidera, Cadent (data safety monitoring board), Adamas (steering committee), Biogen (via the Parkinson Study Group steering committee), Kyowa Kirin (advisory board), Lundbeck (advisory board), Jazz/Cavion (steering committee), Acorda (advisory board), Bial (DMC) and Genentech. CT also declares grant support to her institution from The Michael J. Fox Foundation, National Institute of Health, Gateway LLC, Department of Defense, Roche Genentech, Biogen, Parkinson Foundation and Marcus Program in Precision Medicine. CT declares membership on the npj Parkinson’s Disease Editorial Board. CK declares employment for The Michael J. Fox Foundation. YX declares employment for and travel grants from The Michael J. Fox Foundation. SC declares employment for and travel grants from The Michael J. Fox Foundation. LC-M declares employment for and employee stock options in Amprion, grants 16712 and 21233 from The Michael J. Fox Foundation to his institution; grant U44NS111672 from NIH to his institution; and patents or patent application numbers US 20210277076A1, US 20210311077A1, US 20190353669A1 and US 20210223268A1. PD has no declarations. TF declares travel grants and grant payments to her institution (Indiana University) from The Michael J. Fox Foundation. MF declares employment for The Michael J. Fox Foundation and an unpaid advisory role at Vaxxinity. DJ declares employment for and employee stock options from Denali Therapeutics. KK declares support to his institution (University of Rochester Medical Center) from The Michael J. Fox Foundation. KMe declares consultancies for The Michael J. Fox Foundation, AcuRx, Caraway, Cerebral Therapeutics, NRG Therapeutics (scientific advisory board), Nitrase Therapeutics (scientific advisory board), Nurabio, Retromer Therapeutics (director on the board, part-time chief scientific officer), Schrodinger, Sinopia Biosciences (scientific advisory board), and Vanqua Biosciences (scientific advisory board); stock ownership for Cognition Therapeutics, Eli Lilly (retiree stock holder), Envisagenics, Nitrase Therapeutics, Sinopia Biosciences and Retromer Therapeutics; honoraria for the University of Utah; patents or patent applications for Retromer Therapeutics (planned patent); research grant from The Michael J. Fox Foundation and travel grants from the University of Utah. BM declares consultancies from Roche and Biogen; grants from The Michael J. Fox Foundation, ASAP and DFG; honoraria for Abbvie and Bial; leadership role for The Michael J. Fox Foundation and travel grants for Abbvie. TM declares support to his institution (Stanford University School of Medicine) from The Michael J. Fox Foundation. KN declares grant to her institution from The Michael J. Fox Foundation. JS declares consultancies from Invicro, Biogen, and Abbvie; and stock ownership from RealmIDX, MNI Holdings, and LikeMinds as well as grants from The Michael J. Fox Foundation. TSh declares employment for The Michael J. Fox Foundation. ASin declares employment for The National Institutes of Health who received grants from The Michael J. Fox Foundation and ASAP. ASin declares Diagnostic for Stroke royalties (unrelated to current work); honoraria from Movement Disorders Society and Nature Publishing Group; travel grants from Chan Zuckerberg Initiative, The Michael J. Fox Foundation and Weill Cornell. ASin’s spouse is an employee of GeneDx. ASin declares being an associate editor for the npj Parkinson’s Disease Editorial Board. DS has no declarations. MS declared consultancies for Mediflix, Inc., Health and Wellness Partners; honoraria from Atria Foundation, International Parkinson and Movement Disorder Society, Neurocrine, Luye Pharma and Acorda. MS serves on advisory board at Neuroderm, Alexza, Alexion and Biogen. CS declares employment for Amprion; stock ownership for Amprion; honoraria (will receive royalties for the sale of seed amplification assay [SAA]) from Amprion; and patents or patent applications, awarded and amplified in conjunction with Amprion for the SAA assay. ET has no declarations. ASid declares consultancies for SPARC Therapeutics, Capsida Therapeutics and Parkinson Study Group; honoraria from Bial; grants from The Michael J. Fox Foundation (member of PPMI Steering Committee); and participation on board at Wave Life Sciences, Inhibikase, Prevail, Huntington Study Group and Massachusetts General Hospital. BD declarations are TBD. TSi declares consultancies for AcureX, Adamas, AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson’s Consortium, Denali, The Michael J. Fox Foundation, Neuroderm, Roche, Sanofi, Sinopia, Takeda, and Vanqua Bio; on advisory boards for AcureX, Adamas, AskBio, Biohaven, Denali, GAIN, Neuron23 and Roche; on scientific advisory boards for Koneksa, Neuroderm, Sanofi and UCB; and received research funding from Amneal, Biogen, Roche, Neuroderm, Sanofi, Prevail and UCB and an investigator for NINDS, MJFF, Parkinson’s Foundation. KMa declares support to his institution (Institute for Neurodegenerative Disorders) from The Michael J. Fox Foundation. KMa also declares consultancies for Invicro, The Michael J. Fox Foundation, Roche, Calico, Coave, Neuron23, Orbimed, Biohaven, Anofi, Koneksa, Merck, Lilly, Inhibikase, Neuramedy, IRLabs and Prothena and participates on DSMB at Biohaven.

The floral microenvironment impacts gametophyte viability and plant-pollinator interactions. Plants employ mechanisms to modify floral temperature, including thermogenesis, absorption of solar radiation, and evaporative cooling. Whether floral thermoregulation impacts reproductive fitness, and how floral morphological variation mediates thermoregulatory capacity are poorly understood. We measured temperature of the floral microenvironment in the field and tested for thermogenesis in the lab in early spring flowering Hexastylis arifolia (Aristolochiaceae). We evaluated whether thermoregulatory capacity was associated with floral morphological variation. Finally, we experimentally determined the thermal optimum and tolerance of pollen to assess whether thermoregulation may ameliorate thermal stress to pollen. Pollen germination was optimal near 21 °C, with a 50% tolerance breadth of ~18 °C. In laboratory conditions, flowers exhibited thermogenesis of 1.5-4.8 °C for short intervals within a conserved timeframe (08:00-09:00 h). In the field, temperature inside the floral tube often deviated from ambient - floral interiors were up to 4 °C above ambient when it was cold, but some fell nearly 10 °C below ambient during peak heat. Flowers with smaller openings were cooler and more thermally stable than those with larger openings during peak heat. Thermoregulation maintained a floral microenvironment within the thermal tolerance breadth of pollen. Results suggest that H. arifolia flowers have a stronger capacity to cool than to warm, and that narrower floral openings create a distinct floral microenvironment, enhancing floral cooling effects. While deviation of floral temperature from ambient conditions maintains a suitable environment for pollen and suggests an adaptive role of thermoregulation, we discuss adaptive and nonadaptive mechanisms underlying floral warming and cooling., (© 2024 The Authors. Plant Biology published by John Wiley & Sons Ltd on behalf of German Society for Plant Sciences, Royal Botanical Society of the Netherlands.)

Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life. Neuronal α-synuclein disease is defined by the presence of pathological n-αsyn species detected in vivo (S; the first biological anchor) regardless of the presence of any specific clinical syndrome. On the basis of this definition, we propose that individuals with pathological n-αsyn aggregates are at risk for dopaminergic neuronal dysfunction (D; the second biological anchor). Our biological definition establishes a staging system, the neuronal α-synuclein disease integrated staging system (NSD-ISS), rooted in the biological anchors (S and D) and the degree of functional impairment caused by clinical signs or symptoms. Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). The presence of clinical manifestations marks the transition to stage 2 and beyond. Stage 2 is characterised by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. A biological definition of neuronal α-synuclein disease and an NSD-ISS research framework are essential to enable interventional trials at early disease stages. The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated. Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate., Competing Interests: Declaration of interests TSi declares consultancies for 4D Pharma, Acadia, AcureX, AskBio, Amneal, Blue Rock Therapeutics, Caraway, Critical Path for Parkinson's Consortium, Denali, The Michael J Fox Foundation, Neuroderm, Roche, Sanofi, Sinopia, Sunovion, Takeda, UCB, Vanqua Bio, and Voyager. LMC declares research support and consulting fees from The Michael J Fox Foundation. KP declares consultancies for Curasen; was on a scientific advisory board for Curasen and Amprion; honoraria from invited scientific presentations to universities and professional societies not exceeding $5000 per year from California Congress of Clinical Neurology, California Neurological Society, and Johns Hopkins University; and patents or patent applications numbers 17/314,979 and 63/377,293. KP also declares grants to her institution (Stanford University School of Medicine) from NIH/NINDS NS115114, NS062684, NS075097, NIH/NIA U19 AG065156, P30 AG066515, The Michael J Fox Foundation, Lewy Body Dementia Association, Alzheimer's Drug Discovery Foundation, Sue Berghoff LBD Research Fellowship, and the Knight Initiative for Brain Resilience. MB declares travel grants from The Michael J Fox Foundation. SC declares employment for and travel grants from The Michael J Fox Foundation. The Michael J Fox Foundation received funding support from named non-profit institutions (Cure Parkinson's, Lewy Body Dementia Association, Parkinson Canada, Parkinson's UK, and Shake It Up Australia Foundation) to convene an in-person roundtable of experts in April 2023 in which The Michael J Fox Foundation (employer) cost-shared; The Michael J Fox Foundation (employer) provided funding for an in-person meeting in January, 2023. CC declares grants from The Michael J Fox Foundation and NIH/NINDS. LC-M declares employment for, and employee stock options in, Amprion; grants from The Michael J Fox Foundation; and patents or patent applications (numbers US 20210277076A1, US 20210311077A1, US 20190353669A1, and US 20210223268A1). TD declares former employment of and might hold stock or stock options in Biogen. TF declares travel grants and grant payments to her institution (Indiana University) from The Michael J Fox Foundation. MF declares employment for The Michael J Fox Foundation and an unpaid advisory role at Vaxxinity. CG declares research funding to her institution from The Michael J Fox Foundation. DJ declares employment for and employee stock options from Denali Therapeutics. KK declares support to his institution (University of Rochester Medical Center) from The Michael J Fox Foundation. CK declares employment for and travel grants from The Michael J Fox Foundation. KMe declares consultancies for The Michael J Fox Foundation, AcuRx, Caraway, Cerebral Therapeutics, NRG Therapeutics (scientific advisory board), Nitrase Therapeutics (scientific advisory board), Nurabio, Retromer Therapeutics (director on the board, part-time chief scientific officer), Schrodinger, Sinopia Biosciences (scientific advisory board), and Vanqua Biosciences (scientific advisory board); stock ownership for Cognition Therapeutics, Eli Lilly (retiree stock holder), Envisagenics, Nitrase Therapeutics, Sinopia Biosciences, and Retromer Therapeutics; honoraria for the University of Utah; patents or patent applications for Retromer Therapeutics (planned patent); a research grant from The Michael J Fox Foundation; and travel grants from the University of Utah. BM declares consultancies from Roche, Biogen, and The Michael J Fox Foundation; grants from The Michael J Fox Foundation, ASAP, and DFG; honoraria for AbbVie; and travel grants for AbbVie. TM declares support to his institution (Stanford University School of Medicine) from The Michael J Fox Foundation. KN declares support from The Michael J Fox Foundation. GP declares employment for F Hoffmann-La Roche and stock ownership for F Hoffmann-La Roche, Atea, Novartis, and Eli Lilly. JS declares consultancies from Invicro, Biogen, and AbbVie; and stock ownership from RealmIDX, MNI Holdings, and LikeMinds, as well as grants from The Michael J Fox Foundation. TSh declares employment for The Michael J Fox Foundation. ASin declares employment for NIH who received grants from The Michael J Fox Foundation and ASAP. ASin declares Diagnostic for Stroke royalties (unrelated to current work); honoraria from Movement Disorders Society and Nature Publishing Group; travel grants from Chan Zuckerberg Initiative, The Michael J Fox Foundation, and Weill Cornell. Asin's spouse is an employee of GeneDx. DS has no declarations. MS declared consultancies for Mediflix, and Health and Wellness Partners; honoraria from Atria Foundation, International Parkinson and Movement Disorder Society, Neurocrine, Luye Pharma, and Acorda. MS serves on advisory board at Neuroderm, Alexza, Alexion, and Biogen. CS declares employment for Amprion; stock ownership for Amprion; honoraria (will receive royalties for the sale of seed amplification assay) from Amprion; and patents or patent applications, awarded and amplified in conjunction with Amprion for the seed amplification assay. CT declares consultancies for CNS Ratings, Australian Parkinson's Mission, Biogen, Evidera, Cadent (data safety monitoring board), Adamas (steering committee), Biogen (via the Parkinson Study Group steering committee), Kyowa Kirin (advisory board), Lundbeck (advisory board), Jazz–Cavion (steering committee), Acorda (advisory board), Bial (DMC), and Genentech. CT also declares grant support to UCSF from The Michael J Fox Foundation, National Institute of Health, Gateway, Department of Defense, Roche Genentech, Biogen, Parkinson Foundation, and Marcus Program in Precision Medicine. DW declares salary support from The Michael J Fox Foundation for serving on an executive steering committee for the Parkinson Progression Markers Initiative. YX declares employment for and travel grants from The Michael J Fox Foundation. ASid declares consultancies for SPARC Therapeutics, Capsida Therapeutics, and Parkinson Study Group; honoraria from Bial; grants from The Michael J Fox Foundation (member of Parkinson Progression Markers Initiative steering committee), and NIH; and participation on board at Wave Life Sciences, Inhibikase, Prevail and Huntington Study Group, and Massachusetts General Hospital. BD has received consulting fees and travel support for his role as an advisor for Arch Venture Partners, Cerveau Technologies, Epilepsy Foundation, F-PRIME Capital, Loulou Foundation, and The Michael J Fox Foundation. BD has a leadership or fiduciary role in the Virginia Neurological Society (past president) and Prothena (Director). BD holds stock options with Prothena. KM declares support to his institution (Institute for Neurodegenerative Disorders) from The Michael J Fox Foundation. KMa also declares consultancies for Invicro, The Michael J Fox Foundation, Roche, Calico, Coave, Neuron23, Orbimed, Biohaven, Anofi, Koneksa, Merck, Lilly, Inhibikase, Neuramedy, IRLabs, and Prothena. KMa participates on DSMB at Biohaven. TB, MC, PD, and ET and declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

"Translational medicine" has been a buzzword for over two decades. The concept was intended to be lofty, to reflect a new "bench-to-bedside" approach to basic and clinical research that would bridge fields, close gaps, accelerate innovation, and shorten the time and effort it takes to bring novel technologies from basic discovery to clinical application. Has this approach been successful and lived up to its promise? Despite incredible scientific advances and innovations developed within academia, successful clinical translation into real-world solutions has been difficult. This has been particularly challenging within the pulmonary field, because there have been fewer U.S. Food and Drug Administration-approved drugs and higher failure rates for pulmonary therapies than with other common disease areas. The American Thoracic Society convened a working group with the goal of identifying major challenges related to the commercialization of technologies within the pulmonary space and opportunities to enhance this process. A survey was developed and administered to 164 participants within the pulmonary arena. This report provides a summary of these survey results. Importantly, this report identifies a number of poorly recognized challenges that exist in pulmonary academic settings, which likely contribute to diminished efficiency of commercialization efforts, ultimately hindering the rate of successful clinical translation. Because many innovations are initially developed in academic settings, this is a global public health issue that impacts the entire American Thoracic Society community. This report also summarizes key resources and opportunities and provides recommendations to enhance successful commercialization of pulmonary technologies.

Background: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups., Methods: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson's disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson's disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson's disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex., Findings: This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson's disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson's disease was 87·7% (95% CI 84·9-90·5), and specificity for healthy controls was 96·3% (93·4-99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson's disease with the typical olfactory deficit was 98·6% (96·4-99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson's disease (67·5% [59·2-75·8]) and participants with sporadic Parkinson's disease without olfactory deficit (78·3% [69·8-86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4-48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive., Interpretation: This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson's disease. Our results show that the assay classifies people with Parkinson's disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson's disease and to establish biomarker-defined at-risk cohorts., Funding: PPMI is funded by the Michael J Fox Foundation for Parkinson's Research and funding partners, including: Abbvie, AcureX, Aligning Science Across Parkinson's, Amathus Therapeutics, Avid Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen, BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali, Edmond J Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily, Voyager Therapeutics, and Yumanity., Competing Interests: Declaration of interests AS declares consultancy for Merck, Parkinson Study Group; and honoraria from Bial. LC-M declares employment for Amprion; stock ownership (employee stock options) for Amprion; and patent or patent applications numbers US 20210277076A1, US 20210311077A1, US 20190353669A1, and US 20210223268A1. CMF declares employment for Amprion; stock ownership (employee stock options) for Amprion; and patent or patent applications numbers US 20210277076A1 and US 20210311077A1. YM declares employment for Amprion; stock ownership (employee stock options) for Amprion; and patent or patent applications number US 20210277076A1. PAU declares employment for Amprion; and stock ownership (employee stock options) for Amprion. HN declares employment for Amprion; and stock ownership (employee stock options) for Amprion. RNA declares consultancies for Janssen, Sanofi, Ono Therapuetics, Avrobio, Takeda, Gain Therapuetics, Merck, GlaxoSmithKline, and Caraway. LMC declares honoraria (royalties) from Elsevier and Wolters Kluwel. TF declares travel grants from the Michael J Fox Foundation. KMe declares consultancies for the Michael J Fox Foundation, AcuRx, Caraway, Cerebral Therapeutics, NRG Therapeutics (scientific advisory board), Nurabio, Retromer Therapeutics (director on the board, part-time chief scientific officer), Schrodinger, Sinopia Biosciences (scientific advisory board), and Vanqua Biosciences (scientific advisory board); stock ownership for Cognition Therapeutics, Eli Lilly (retiree stock holder), Envisagenics, and Retromer Therapeutics; honoraria for the University of Utah; patents or patent applications for Retromer Therapeutics (planned patent); and travel grants from the University of Utah. BM declares consultancies from Roche, Biogen, and the Michael J Fox Foundation; honoraria for Abbvie; and travel grants for Abbvie. KLP declares consultancies for Curasen; was on a scientific advisory board for Curasen and Amprion; honoraria from invited scientific presentations to universities and professional societies not exceeding $5000 per year from California Congress of Clinical Neurology, California Neurological Society, and Johns Hopkins University; and patents or patent applications numbers 17/314,979 and 63/377,293. JS declares consultancies from Invicro, Biogen, and Abbvie; and stock ownership from RealmIDX, MNI Holdings, and LikeMinds. TSi declares consultancies for 4D Pharma, Acadia, AcureX, AskBio, Amneal, Blue Rock Therapeutics, Caraway, Critical Path for Parkinson's Consortium, Denali, Michael J Fox Foundation, Neuroderm, Roche, Sanofi, Sinopia, Sunovion, Takeda, UCB, Vanqua Bio, and Voyager. CMT declares consultancies for CNS Ratings, Australian Parkinson's Mission, Biogen, Evidera, Cadent (data safety monitoring board), Adamas (steering committee), Biogen (via the Parkinson Study Group steering committee), Kyowa Kirin (advisory board), Lundbeck (advisory board), Jazz/Cavion (steering committee), and Acorda (advisory board). DW declares receiving salary support from Michael J Fox Foundation for serving on an Executive Steering Committee for the PPMI. AV declares consultancies for CoA Therapeutics, XW Pharma, and Biogen. MF declares employment for the Michael J Fox Foundation. LMAO declares employment for the Michael J Fox Foundation. SJH declares employment for the Michael J Fox Foundation. TSh declares employment for the Michael J Fox Foundation. KMa declares consultancies for Invicro, MJFF, Roche, Calico, Coave, Neuron23, Orbimed, Neuroderm, Sanofi, Takeda, Merck, Lilly, Inhibikase, and Neuramedy. CS declares employment for Amprion; stock ownership for Amprion; honoraria (will receive royalties for the sale of seed amplification assay [SAA]) from Amprion; and patents or patent applications, awarded and amplified in conjunction with Amprion for the SAA assay., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We quantified concentrations of three isoforms of the endolysosomal lipid, bis(monoacylglycerol) phosphate (BMP) in the urine of deeply phenotyped cohorts in the Parkinson's Progression Markers Initiative: LRRK2 G2019S PD (N = 134) and non-manifesting carriers (NMC) (G2019S+ NMC; N = 182), LRRK2 R1441G PD (N = 15) and R1441G+ NMC (N = 15), GBA1 N409S PD (N = 76) and N409S+ NMC (N = 178), sporadic PD (sPD, N = 379) and healthy controls (HC) (N = 190). The effects of each mutation and disease status were analyzed using nonparametric methods. Longitudinal changes in BMP levels were analyzed using linear mixed models. At baseline, all LRRK2 carriers had 3-7× higher BMP levels compared to HC, irrespective of the disease status. GBA1 N409S carriers also showed significant, albeit smaller, elevation (~30-40%) in BMP levels compared to HC. In LRRK2 G2019S PD, urinary BMP levels remained stable over two years. Furthermore, baseline BMP levels did not predict disease progression as measured by striatal DaT imaging, MDS-UPDRS III Off, or MoCA in any of the cohorts. These data support the utility of BMP as a target modulation biomarker in therapeutic trials of genetic and sPD but not as a prognostic or disease progression biomarker., (© 2023. The Author(s).)

The Parkinson's disease (PD) research field has seen the advent of several promising biomarkers and a deeper understanding of the clinical features of the disease from the earliest stages of pathology to manifest disease. Despite progress, a biologically based PD staging system does not exist. Such staging would be a useful framework within which to model the disease, develop and validate biomarkers, guide therapeutic development, and inform clinical trials design. We propose that the presence of aggregated neuronal α-synuclein, dopaminergic neuron dysfunction/degeneration, and clinical signs and symptoms identifies a group of individuals that have Lewy body pathology, which in early stages manifests with what is now referred to as prodromal non-motor features and later stages with the manifestations of PD and related Lewy body diseases as defined by clinical diagnostic criteria. Based on the state of the field, we herein propose a definition and staging of PD based on biology. We present the biologic basis for such a staging system and review key assumptions and evidence that support the proposed approach. We identify gaps in knowledge and delineate crucial research priorities that will inform the ultimate integrated biologic staging system for PD.

We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson's Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as <65% of age/sex-expected lowest putamen SBR) and 11% had hyposmia (defined as ≤15th percentile for age and sex). Only 5 of 176 LRRK2 NMCs developed PD during follow-up. Although NMCs scored significantly worse on numerous clinical scales at baseline than HCs, there was no longitudinal change in any clinical measures over 2 years or in DAT binding. There were no longitudinal differences in CSF and serum biomarkers between NMCs and HCs. Urinary BMP was significantly elevated in NMCs at all time points but did not change longitudinally. Neither baseline biofluid biomarkers nor the presence of DAT deficit correlated with 2-year change in clinical outcomes. We observed no significant 2-year longitudinal change in clinical or biomarker measures in LRRK2 G2019S NMCs in this large, well-characterized cohort even in the participants with baseline DAT deficit. These findings highlight the essential need for further enrichment biomarker discovery in addition to DAT deficit and longer follow-up to enable the selection of NMCs at the highest risk for conversion to enable future prevention clinical trials., (© 2022. The Author(s).)

Importance: The Global Burden of Disease study conducted between 1990 and 2016, based on a global study of 195 countries and territories, identified Parkinson disease (PD) as the fastest growing neurological disorder when measured using death and disability. Most people affected by PD live in low- and middle-income countries (LMICs) and experience large inequalities in access to neurological care and essential medicines. This Special Communication describes 6 actions steps that are urgently needed to address global disparities in PD., Observations: The adoption by the 73rd World Health Assembly (WHA) of resolution 73.10 to develop an intersectoral global action plan on epilepsy and other neurological disorders in consultation with member states was the stimulus to coordinate efforts and leverage momentum to advance the agenda of neurological conditions, such as PD. In April 2021, the Brain Health Unit at the World Health Organization convened a multidisciplinary, sex-balanced, international consultation workshop, which identified 6 workable avenues for action within the domains of disease burden; advocacy and awareness; prevention and risk reduction; diagnosis, treatment, and care; caregiver support; and research., Conclusions and Relevance: The dramatic increase of PD cases in many world regions and the potential costs of PD-associated treatment will need to be addressed to prevent possible health service strain. Across the board, governments, multilateral agencies, donors, public health organizations, and health care professionals constitute potential stakeholders who are urged to make this a priority.

Sharing clinical trial data can provide value to research participants and communities by accelerating the development of new knowledge and therapies as investigators merge data sets to conduct new analyses, reproduce published findings to raise standards for original research, and learn from the work of others to generate new research questions. Nonprofit funders, including disease advocacy and patient-focused organizations, play a pivotal role in the promotion and implementation of data sharing policies. Funders are uniquely positioned to promote and support a culture of data sharing by serving as trusted liaisons between potential research participants and investigators who wish to access these participants' networks for clinical trial recruitment. In short, nonprofit funders can drive policies and influence research culture. The purpose of this paper is to detail a set of aspirational goals and forward thinking, collaborative data sharing solutions for nonprofit funders to fold into existing funding policies. The goals of this paper convey the complexity of the opportunities and challenges facing nonprofit funders and the appropriate prioritization of data sharing within their organizations and may serve as a starting point for a data sharing toolkit for nonprofit funders of clinical trials to provide the clarity of mission and mechanisms to enforce the data sharing practices their communities already expect are happening., (©Timothy Coetzee, Mad Price Ball, Marc Boutin, Abby Bronson, David T Dexter, Rebecca A English, Patricia Furlong, Andrew D Goodman, Cynthia Grossman, Adrian F Hernandez, Jennifer E Hinners, Lynn Hudson, Annie Kennedy, Mary Jane Marchisotto, Elizabeth Myers, W Benjamin Nowell, Brian A Nosek, Todd Sherer, Carolyn Shore, Ida Sim, Luba Smolensky, Christopher Williams, Julie Wood, Sharon F Terry, Lynn Matrisian. Originally published in Journal of Participatory Medicine (http://jopm.jmir.org), 29.03.2021.)

Background: Commentators suggest that patients have unrealistic expectations about the pace of research advances and that such expectations interfere with patient decision-making., Objective: The objective of this study was to compare expert expectations about the timing of research milestone attainment with those of patients who follow Parkinson's disease (PD) research., Methods: Patients with PD and experts were asked to provide forecasts about 11 milestones in PD research in an online survey. PD experts were identified from a Michael J. Fox Foundation database, highly ranked neurology centers in the United States and Canada, and corresponding authors of articles on PD in top medical journals. Patients with PD were recruited through the Michael J. Fox Foundation. We tested whether patient forecasts differed on average from expert forecasts. We also tested whether differences between patient forecasts and the average expert forecasts were associated with any demographic factors., Results: A total of 256 patients and 249 PD experts completed the survey. For 9 of the 11 milestones, patients' forecasts were on average higher than those of experts. Only exercise therapy met our 10% difference threshold for practical significance. Education was the only demographic that predicted patient deviations from expert forecasts on milestone forecasts. Patients offered significantly higher forecasts than experts that the clinical trials used in milestone queries would report positive primary outcomes., Conclusions: Differences between patient and expert expectations about research milestones were generally minor, suggesting that there is little cause for concern that patients who follow PD research are unduly swayed by inaccurate representations of research advancement in the media or elsewhere. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

A fundamental question in advancing Parkinson disease (PD) research is whether it represents one disorder or many. Does each genetic PD inform a common pathobiology or represent a unique entity? Do the similarities between genetic and idiopathic forms of PD outweigh the differences? If aggregates of α-synuclein in Lewy bodies and Lewy neurites are present in most (α-synucleinopathies), are they also etiopathogenically significant in each (α-synuclein pathogenesis)? Does it matter that postmortem studies in PD have demonstrated that mixed protein-aggregate pathology is the rule and pure α-synucleinopathy the exception? Should we continue to pursue convergent biomarkers that are representative of the diverse whole of PD or subtype-specific, divergent biomarkers, present in some but absent in most? Have clinical trials that failed to demonstrate efficacy of putative disease-modifying interventions been true failures (shortcomings of the hypotheses, which should be rejected) or false failures (shortcomings of the trials; hypotheses should be preserved)? Each of these questions reflects a nosologic struggle between the lumper's clinicopathologic model that embraces heterogeneity of one disease and the splitter's focus on a pathobiology-specific set of diseases. Most important, even if PD is not a single disorder, can advances in biomarkers and disease modification be revised to concentrate on pathologic commonalities in large, clinically defined populations? Or should our efforts be reconstructed to focus on smaller subgroups of patients, distinguished by well-defined molecular characteristics, regardless of their phenotypic classification? Will our clinical trial constructs be revised to target larger and earlier, possibly even prodromal, cohorts? Or should our trials efforts be reconstructed to target smaller but molecularly defined presymptomatic or postsymptomatic cohorts? At the Krembil Knowledge Gaps in Parkinson's Disease Symposium, the tentative answers to these questions were discussed, informed by the failures and successes of the fields of breast cancer and cystic fibrosis., (© 2020 American Academy of Neurology.)

Background: Projections about when research milestones will be attained are often of interest to patients and can help inform decisions about research funding and health system planning., Objective: To collect aggregated expert forecasts on the attainment of 11 major research milestones in Parkinson's disease (PD)., Methods: Experts were asked to provide predictions about the attainment of 11 milestones in PD research in an online survey. PD experts were identified from: 1) The Michael J. Fox Foundation for Parkinson's Research data base, 2) doctors specializing in PD at top ranked neurology centers in the US and Canada, and 3) corresponding authors of articles on PD in top medical journals. Judgments were aggregated using coherence weighting. We tested the relationship between demographic variables and individual judgments using a linear regression., Results: 249 PD experts completed the survey. In the aggregate, experts believed that new treatments like gene therapy for monogenic PD, immunotherapy and cell therapy had 56.1%, 59.7%, and 66.6% probability, respectively of progressing in the clinical approval process within the next 10 years. Milestones involving existing management approaches, like the approval of a deep brain stimulation device or a body worn sensor had 78.4% and 82.2% probability of occurring within the next 10 years. Demographic factors were unable to explain deviations from the aggregate forecast (R2 = 0.029)., Conclusions: Aggregated expert opinion suggests that milestones for the advancement of new treatment options for PD are still many years away. However, other improvements in PD diagnosis and management are believed to be near at hand.

Objective: To determine the feasibility, safety and tolerability of lumbar punctures (LPs) in research participants with early Parkinson disease (PD), subjects without evidence of dopaminergic deficiency (SWEDDs) and healthy volunteers (HC)., Background: Cerebrospinal fluid (CSF) analysis is becoming an essential part of the biomarkers discovery effort in PD with still limited data on safety and feasibility of serial LPs in PD participants., Design/methods: Parkinson's Progression Marker Initiative (PPMI) is a longitudinal observation study designed to identify PD progression biomarkers. All PPMI participants undergo LP at baseline, 6, 12 months and yearly thereafter. CSF collection is performed by a trained investigator using predominantly atraumatic needles. Adverse events (AEs) are monitored by phone one week after LP completion. We analyzed safety data from baseline LPs., Results: PPMI enrolled 683 participants (423 PD/196 HC/64 SWEDDs) from 23 study sites. CSF was collected at baseline in 97.5% of participants, of whom 5.4% underwent collection under fluoroscopy. 23% participants reported any related AEs, 68% of all AE were mild while 5.6% were severe. The most common AEs were headaches (13%) and low back pain (6.5%) and both occurred more commonly in HC and SWEDDs compared to PD participants. Factors associated with higher incidence of AEs across the cohorts included female gender, younger age and use of traumatic needles with larger diameter. AEs largely did not impact compliance with the future LPs., Conclusions: LPs are safe and feasible in PD research participants. Specific LP techniques (needle type and gauge) may reduce the overall incidence of AEs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts., (© 2019 American Academy of Neurology.)

Objective: The Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker-defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease-modifying therapeutic trials., Methods: A total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org., Results: Approximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD. The total MDS-UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cerebrospinal fluid (CSF) was acquired from >97% of all subjects. CSF (PD/HC/SWEDD pg/mL) α-synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD ( P  < 0.03). Similarly, t -tau (45/53) and p -tau (16/18) were reduced in PD versus HC ( P  < 0.01)., Interpretation: PPMI has detailed the biomarker signature for an early PD cohort defined by clinical features and imaging biomarkers. This strategy provides the framework to establish biomarker cohorts and to define longitudinal progression biomarkers to support future PD treatment trials.

The recent advent of an "ecosystem" of shared biofluid sample biorepositories and data sets will focus biomarker efforts in Parkinson's disease, boosting the therapeutic development pipeline and enabling translation with real-world impact., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: The objective of this study was to assess longitudinal change in clinical and dopamine transporter imaging outcomes in early, untreated PD., Methods: We describe 5-year longitudinal change of the MDS-UPDRS and other clinical measures using results from the Parkinson's Progression Markers Initiative, a longitudinal cohort study of early Parkinson's disease (PD) participants untreated at baseline. We also provide data on the longitudinal change in dopamine transporter 123-I Ioflupane striatal binding and correlation between the 2 measures., Results: A total of 423 PD participants were recruited, and 358 remain in the study at year 5. Baseline MDS-UPDRS total score was 32.4 (standard deviation 13.1), and the average annual change (assessed medications OFF for the treated participants) was 7.45 (11.6), 3.11 (11.7), 4(11.9), 4.7 (11.1), and 1.74(11.9) for years 1, 2, 3, 4, and 5, respectively (P < .0001 for the change over time), with a steeper change in year 1. Dopaminergic therapy had a significant effect on the change of MDS-UPDRS. There was a significant longitudinal change in dopamine transporter binding in all striatal regions (P < .001). There was a significant but weak correlation between MDS-UPDRS and dopamine transporter binding at baseline and years 1, 2, and 4, but no correlation between the rate of change of the 2 variables., Conclusions: We present 5-year longitudinal data on the change of the MDS-UPDRS and other clinical and dopamine transporter imaging outcome measures in early PD. These data can be used for sample size estimates for interventional studies in the de novo PD population. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Neurological disorders are now the leading source of disability globally, and the fastest growing neurological disorder in the world is Parkinson disease. From 1990 to 2015, the number of people with Parkinson disease doubled to over 6 million. Driven principally by aging, this number is projected to double again to over 12 million by 2040. Additional factors, including increasing longevity, declining smoking rates, and increasing industrialization, could raise the burden to over 17 million. For most of human history, Parkinson has been a rare disorder. However, demography and the by-products of industrialization have now created a Parkinson pandemic that will require heightened activism, focused planning, and novel approaches.

The field of neuroscience is enjoying a rapid expansion in scope, coupled with a remarkable broadening of conceptual approaches, scientific tools, and clinical applications. This growth poses new challenges for academic training programs as they prepare young neuroscientists for a more complex, competitive, and diverse career landscape. Multiple stakeholders, including academia, federal funding agencies, industry, scientific societies, private foundations, and other public and private sector contributors, need to be actively engaged in supporting this broad training effort. A renewed commitment to a more forward-looking, flexible yet integrative training vision offers opportunities for a bright future for young neuroscientists as they assume the role of vanguard of the enterprise that enriches our understanding of the brain., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Inhibition of the kinase activity of leucine-rich repeat kinase 2 (LRRK2) is under investigation as a possible treatment for Parkinson's disease. However, there is no clinical validation as yet, and the safety implications of targeting LRRK2 kinase activity are not well understood. We evaluated the potential safety risks by comparing human and mouse LRRK2 mRNA tissue expression, by analyzing a Lrrk2 knockout mouse model, and by testing selective brain-penetrating LRRK2 kinase inhibitors in multiple species. LRRK2 mRNA tissue expression was comparable between species. Phenotypic analysis of Lrrk2 knockout mice revealed morphologic changes in lungs and kidneys, similar to those reported previously. However, in preclinical toxicity assessments in rodents, no pulmonary or renal changes were induced by two distinct LRRK2 kinase inhibitors. Both of these kinase inhibitors induced abnormal cytoplasmic accumulation of secretory lysosome-related organelles known as lamellar bodies in type II pneumocytes of the lung in nonhuman primates, but no lysosomal abnormality was observed in the kidney. The pulmonary change resembled the phenotype of Lrrk2 knockout mice, suggesting that this was LRRK2-mediated rather than a nonspecific or off-target effect. A biomarker of lysosomal dysregulation, di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP), was also decreased in the urine of Lrrk2 knockout mice and nonhuman primates treated with LRRK2 kinase inhibitors. Our results suggest a role for LRRK2 in regulating lysosome-related lamellar bodies and that pulmonary toxicity may be a critical safety liability for LRRK2 kinase inhibitors in patients., (Copyright © 2015, American Association for the Advancement of Science.)

Background: As in other therapeutic areas, clinical studies in Parkinson's disease (PD) face significant recruitment challenges. However, qualitative surveys suggest that individuals with PD are willing to participate in clinical research. The Michael J. Fox Foundation therefore established Fox Trial Finder in 2011 to facilitate connection between PD research teams and volunteers., Objective: Characterize the research volunteers (with and without PD) registered on Fox Trial Finder as of June 2014, and the published, recruiting studies to identify trends and highlight gaps between research requirements and available volunteers., Methods: Profiles of volunteers with and without PD were analyzed to explore trends in geography, demographics, family history and, for those volunteers with PD, disease progression and treatment history. Clinical study profiles were analyzed to determine study type, phase, sponsor, focus, location and eligibility criteria. The analysis focused on volunteers and studies based in the United States., Results: The database contained 26,261 US-based volunteers, including 19,243 volunteers (73%) with PD and 7,018 (27%) controls without PD. The average time since diagnosis for PD volunteers was 5.7 years and the average age at diagnosis was 58 years. Control volunteers were more likely than volunteers with PD to be female (67% vs. 35%) and to have a family history of PD (49% vs. 12%)., Conclusions: Fox Trial Finder's registration history to date demonstrates the high level of willingness among individuals affected by PD to participate in clinical research and provide a significant amount of personal health information to facilitate that participation.

Background: Fox Trial Finder is an online registry for individuals with and without Parkinson disease (PD) interested in participating in PD research. However, distance or disability could prevent such individuals from participating in traditional, clinic-based research at major centers., Objective: Use videoconferencing to connect participants to specialists to: (1) demonstrate feasibility of virtual research visits within this population (2) collect phenotypic data of the participants, (3) validate self-reported diagnosis, and (4) gauge interest in virtual research visits., Methods: We solicited volunteers throughout the United States through Fox Trial Finder. Interested individuals with PD provided consent, were given web cameras if needed, completed baseline surveys, and downloaded videoconferencing software remotely. Participants had a test connection and assessment appointment which included the Montreal Cognitive Assessment (MoCA), then a virtual research visit with a neurologist who reviewed their history and assessed their PD using a modified Movement Disorders Society Unified Parkinson's Disease Rating Scale. Neurologists assessed PD diagnosis and symptomatology. Physicians and participants were surveyed about their experience., Results: Of 204 individuals who consented, 166 (81% ) individuals from 39 states completed all visits. The mean age was 62 and mean disease duration was 8.0 years. Mean MoCA score was 26.5, and mean modified MDS-UPDRS motor score was 22.8 (out of a possible 124). Neurologists judged PD as the most likely diagnosis in 97% of cases. Overall satisfaction with the visits was 79% (satisfied or very satisfied) among neurologists and 93% among participants., Conclusions: Through virtual research visits, neurologists engaged, characterized, and validated self-reported diagnosis in individuals with PD over a broad geography. This model may facilitate future research participation.

Several large pharmaceutical companies have selectively downsized their neuroscience research divisions, reflecting a growing view that developing drugs to treat brain diseases is more difficult and often more time-consuming and expensive than developing drugs for other therapeutic areas, and thus represents a weak area for investment. These withdrawals reduce global neuroscience translational capabilities and pose a serious challenge to society's interests in ameliorating the impact of nervous system diseases. While the path forward ultimately lies in improving understandings of disease mechanisms, many promising therapeutic approaches have already been identified, and rebalancing the underlying risk/reward calculus could help keep companies engaged in making CNS drugs. One way to do this that would not require upfront funding is to change the policies that regulate market returns for the most-needed breakthrough drugs. The broader neuroscience community including clinicians and patients should convene to develop and advocate for such policy changes., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Academic technology transfer in its current form began with the passage of the Bayh-Dole Act in 1980, which allowed universities to retain ownership of federally funded intellectual property. Since that time, a profession has evolved that has transformed how inventions arising in universities are treated, resulting in significant impact to US society. While there have been a number of articles highlighting benefits of technology transfer, now, more than at any other time since the Bayh-Dole Act was passed, the profession and the impacts of this groundbreaking legislation have come under intense scrutiny. This article serves as an examination of the many positive benefits and evolution, both financial and intrinsic, provided by academic invention and technology transfer, summarized in Table 1.

Repurposing Food and Drug Administration (FDA)-approved drugs for a new indication may offer an accelerated pathway for new treatments to patients but is also fraught with significant commercial, regulatory, and reimbursement challenges. The Alzheimer's Drug Discovery Foundation (ADDF) and the Michael J. Fox Foundation for Parkinson's Research (MJFF) convened an advisory panel in October 2013 to understand stakeholder perspectives related to repurposing FDA-approved drugs for neurodegenerative diseases. Here, we present opportunities on how philanthropy, industry, and government can begin to address these challenges, promote policy changes, and develop targeted funding strategies to accelerate the potential of FDA-approved repurposed drugs.

Therapeutic development in Parkinson's disease is hampered by the paucity of well-validated biomarkers that can assist with diagnosis and/or tracking the progression of the disease. Since its inception, the Michael J Fox Foundation for Parkinson's Research has invested heavily in biomarker research and continues to prioritize discovery and development efforts. This article summarizes the history and evolution of the Michael J Fox Foundation's role in supporting biomarker research and lays out the current challenges in successfully developing markers that can be used to test therapies, while also providing a vision of future funding efforts in Parkinson's disease biomarkers.

Funding for biomedical and neuroscience research has increased over the last decade but without a concomitant increase in new therapies. This study's objectives were to determine the level and principal sources of recent funding for Parkinson disease (PD) research and to determine the current state of PD drug development. We determined the level and principal sources of recent funding for PD research from the following sources: US federal agencies, large PD foundations based in the United States, and global industry. We assessed the status of PD drug development through the use of a proprietary drug pipeline database. Funding for PD research from the sources examined was approximately $1.1 billion in 2003 and $1.2 billion in 2005. Industry accounted for 77% of support from 2003 to 2005. The number of drugs in development for PD increased from 67 in 2003 to 97 in 2007. Of the companies with at least one compound in development for PD in 2007, most were small (62% had annual revenue of less than $100 million), and most (53%) were based outside the United States. These companies will likely require partnerships to drive successful development of new PD therapies.

Chronic infusion of rotenone (Rot) to Lewis rats reproduces many features of Parkinson disease. Rot (3 mg/kg/day) was infused subcutaneously to male Lewis rats for 6 days using Alzet minipumps. Control rats received the vehicle only. Presence of 0.1% bovine serum albumin during the isolation procedure completely removed rotenone bound to the mitochondria. Therefore all functional changes observed were aftereffects of rotenone toxicity in vivo. In Rot rat brain mitochondria (Rot-RBM) there was a 30-40% inhibition of respiration in State 3 and State 3U with Complex I (Co-I) substrates and succinate. Rot did not affect the State 4Deltapsi of RBM and rat liver mitochondria (RLM). However, Rot-RBM required two times less Ca2+ to initiate permeability transition (mPT). There was a 2-fold increase in O*2- or H2O2 generation in Rot-RBM oxidizing glutamate. Rot infusion affected RLM little. Our results show that in RBM, the major site of reactive oxygen species generation with glutamate or succinate is Co-I. We also found that Co-II generates substantial amounts of reactive oxygen species that increased 2-fold in the Rot-RBM. Our data suggest that the primary mechanism of the Rot toxic effect on RBM consists in a significant increase of O*2- generation that causes damage to Co-I and Co-II, presumably at the level of 4Fe-4S clusters. Decreased respiratory activity diminishes resistance of RBM to Ca2+ and thus increases probability of mPT and apoptotic cell death. We suggest that the damage to Co-I and Co-II shifts O*2- generation from the CoQ10 sites to more proximal sites, such as flavines, and makes it independent of the RBM functional state.

Complex I of the mammalian electron transfer chain is composed of at least 43 protein subunits, of which 7 are encoded by mtDNA. It catalyzes the transfer of electrons from NADH to ubiquinone and translocates protons from the mitochondrial matrix to the intermembrane space. It may also play direct roles in the mitochondrial permeability transition and in cell death pathways. Despite the limitations of current complex I assays, biochemical studies have suggested the presence of a mild, systemic defect of complex I in Parkinson's disease (PD). Recent experimental work has modeled this abnormality using rotenone to systemically inhibit complex I. Chronic rotenone exposure accurately recapitulated the pathological, biochemical, and behavioral features of PD. Thus, relatively subtle complex I abnormalities--either genetic or acquired--may be central to the pathogenesis of PD.

Parkinson's disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway and the appearance of cytoplasmic proteinaceous aggregates known as Lewy bodies. Studies of familial PD have uncovered rare causative mutations in genes, including alpha-synuclein. Mutations or oxidative modification of alpha-synuclein causes it to aggregate; alpha-synuclein is a major component of the Lewy body in both familial and sporadic PD. Biochemical analysis has implicated mitochondrial dysfunction in PD. Epidemiological studies indicate a role of exposure to pesticides, some of which are mitochondrial toxins. Mitochondrial dysfunction, resulting from genetic defects, environmental toxins, or a combination of the two, may cause alpha-synuclein aggregation and produce selective neurodegeneration through mechanisms involving oxidative stress and excitotoxicity. Efforts to better define PD pathogenesis should reveal novel therapeutic targets.

Sporadic, non-familial Parkinson's disease is characterized by a 15-30% reduction in complex I activity of the electron transport chain. A pharmacological model of reduced complex I activity was created by prolonged treatment of SH-SY5Y cells with low doses (5-20 nM) of rotenone, a selective inhibitor of complex I. Short-term (less than 2 week) exposure to rotenone did not influence calcium signaling, production of reactive oxygen species, or mitochondrial morphology. However, following 2 weeks of rotenone exposure, SH-SY5Y cells showed unusual calcium dynamics, specifically multiple calcium responses to carbachol, a muscarinic agonist. These secondary calcium responses were not seen in control SH-SY5Y cells and were dependent upon calcium influx. Mitochondrial membrane potential was also reduced in low dose rotenone-treated cells. These results demonstrate that a chronic, partial reduction in complex I activity, such as that seen in Parkinson's disease, can alter cell signaling events and perhaps increase the susceptibility of cells to calcium overload and subsequent cell death.

The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.

To investigate the role of chronic mitochondrial dysfunction on intracellular calcium signaling, we studied basal and stimulated cytosolic calcium levels in SH-SY5Y cells and a derived cell line devoid of mitochondrial DNA (Rho degrees ). Basal cytosolic calcium levels were slightly but significantly reduced in Rho degrees cells. The impact of chronic depletion of mitochondrial DNA was more evident following exposure of cells to carbachol, a calcium mobilizing agent. Calcium transients generated in Rho degrees cells following application of carbachol were more rapid than those in SH-SY5Y cells. A plateau phase of calcium recovery during calcium transients was present in SH-SY5Y cells but absent in Rho degrees cells. The rapid calcium transients in Rho degrees cells were due, in part, to increased reliance on Na(+)/Ca(2+) exchange activity at the plasma membrane and the plateau phase in calcium recovery in SH-SY5Y cells was dependent on the presence of extracellular calcium. We also examined whether mitochondrial DNA depletion influenced calcium responses to release of intracellular calcium stores. Rho degrees cells showed reduced responses to the uncoupler, FCCP, and the sarcoplasmic reticulum calcium ATPase inhibitor, thapsigargin. Acute exposure of SH-SY5Y cells to mitochondrial inhibitors did not mimic the results seen in Rho degrees cells. These results suggest that cytosolic calcium homeostasis in this neuron-like cell line is significantly altered as a consequence of chronic depletion of mitochondrial DNA.

Bladder and vascular smooth muscle cells cultured from four rat strains (WKY, SHR, WKHA, WKHT) differing in rates of nerve growth factor (NGF) production were used to determine whether a relationship exists between intracellular calcium and NGF secretion. Basal cytosolic calcium was related to basal NGF secretion rates in bladder and vascular smooth muscle cells from all four strains with the exception of WKHT bladder muscle cells. Thrombin is a calcium-mobilizing agent and increases NGF production from vascular but not bladder smooth muscle cells. Strain differences were found in the magnitude of the calcium peak induced by thrombin in vascular smooth muscle cells, but these differences did not correlate with NGF secretion. Thrombin caused a calcium response in bladder smooth muscle cells without influencing NGF production. Quenching the calcium transient with a calcium chelator had no effect on thrombin-inducted NGF secretion rates in vascular smooth muscle cells. Thus, basal intracellular calcium may establish a set point for NGF secretion from smooth muscle. In addition, transient elevations in cytosolic calcium were unrelated to the induction of NGF output.

Ht30/=Ht5). Cells with reduced mitochondrial activity also showed abnormal responses to the stimulation of NGF output. Thrombin and phorbol ester elevated NGF production from Ht100, Ht30 and Ht10 cells, but not from Ht5 cells. Ht30 cells, despite secreting less NGF basally than Ht100 cells, reached a similar or greater NGF output upon stimulation. Mitogens increased NGF output and NGF mRNA levels with the largest effect on NGF protein in Ht30 cells. Free radical production and the ability of cells to respond to NGF-inducing agents were related. These data suggest that chronic impairment of mitochondrial function associates with disturbances in cellular production of a signaling protein.

Recent epidemiological studies have shown that hypertensive men are more likely to undergo surgical intervention for irritative voiding symptoms from BPH than age-matched controls. Indeed, noradrenergic nerves which regulate vascular tone also participate in the functional component of bladder outlet obstruction due to BPH. Newer, less invasive therapies for BPH such as thermal therapy can relieve symptoms yet do not eliminate obstruction based on urodynamic studies. Coincidentally, drugs such as alpha-adrenoceptor antagonists, which have been thought to relieve obstruction due to a peripheral effect, can be given intrathecally in animals to relieve urinary frequency due to obstruction. Taken together these observations implicate both peripheral and central sympathetic pathways in the motor control of the urinary bladder especially with disease states. We have used the hypertensive and behaviourally hyperactive spontaneously hypertensive rat (SHR), to investigate the roles sympathetic pathways or micturition. Elevated nerve growth factor (NGF) derived from vascular and bladder smooth muscle cells of the SHR appears to direct morphological, biochemical, and functional changes. The increase in NGF can apparently be explained by stabilization of its mRNA leading to increased synthesis in NGF. Bladders from SHRs develop a profuse noradrenergic hyperinnervation compared with the control WKY strain. Since afferents supplying the SHR bladder are hypertrophied, changes in afferent pathways are also likely. These differences in innervation and NGF in the SHR may explain changes in function. SHRs void 3 times as frequently as their genetic controls. Urinary frequency can be reduced by alpha-adrenoceptor antagonists. Cystometrograms performed in SHRs reveal lower bladder capacities and micturition volumes and the presence of unstable contractions compared with the WKY rat. Intrathecal, rather than intra-arterial administration of the alpha-adrenoceptor antagonist doxazosin reduces unstable contractions in the SHR. In vitro muscle bath studies have shown enhanced responses of SHR bladder smooth muscle to alpha-adrenoceptor agonists. It is likely that upregulation of NGF production causes sensory and possibly noradrenergic pathways to elicit hyperactive voiding. Increase in NGF in the adult bladder due to pathological conditions yields similar, yet distinct, consequences for voiding behaviour and innervation. Likewise, increased NGF in adult bladders following obstruction or inflammation triggers neuronal hypertrophy, enhanced reflex activity and urinary frequency. In contrast to the SHR, hyper-innervation is not observed. Moreover, peripheral or spinal alpha-adrenoceptor blockade eliminates urinary frequency following obstruction. These observations support the role for sympathetic pathways in the motor function of the bladder, especially in congenital or adult disease states. A similar process may underlie the neuroplasticity involved in alterations after obstruction or inflammation of the lower urinary tract in humans. The SHR strain raises the possibility that a common genetic defect exists capable of predisposing to both hypertension and overactivity of the urinary bladder. Whether a genetic predisposition to sustained bladder overactivity in response to inflammatory stimuli in obstruction exists in humans is an intriguing prospect.

Altered nerve growth factor (NGF) regulation has been linked to the pathophysiology of hypertension. Vascular smooth muscle cells from an inbred hypertensive, but normoactive rat strain (WKHT) secreted NGF at a greater rate than from a hyperactive, normotensive strain (WKHA). Exposure to phorbol ester increased NGF secretion rates from WKHT by 400-800% but not from WKHA vascular muscle. NGF secretion rates from both WKHT and WKHA vascular cells were elevated by co-application of platelet-derived growth factor (PDGF) and transforming growth factor-beta1 (TGF-beta1) by 300-1000%. This response was partially attenuated by actinomycin D, an inhibitor of RNA transcription. These results suggest that regulation of NGF production does not occur solely at the level of transcription and post-transcriptional mechanisms operate. Analysis of NGF mRNA stability in the two strains following PDGF and TGF-beta1 treatment showed that NGF mRNA in WKHT had a half-life of 126.2+/-11.68 min while in WKHA vascular smooth muscle cells, the half-life was 47. 33+/-11.98 min. In addition to increased NGF mRNA stability in WKHT vascular muscle, these cells have an increased translational efficiency of NGF protein; elevated synthesis of NGF protein per unit NGF mRNA. Differences in signaling pathways may result in increased NGF mRNA stability and translational efficiency that may account for the elevated NGF protein in WKHT vascular smooth muscle cells., (Copyright 1998 Elsevier Science B.V.)

The spontaneously hypertensive rat (SHR) was developed as a genetic model of essential hypertension. In vivo and in vitro evidence demonstrates that vascular smooth muscle cells (VSMCs) from the SHR produce more nerve growth factor (NGF) than the normotensive Wistar-Kyoto (WKY) control strain. This increased NGF production is accompanied by excessive innervation of target tissues in the SHR. In the present study, a sensitive, competitive, quantitative, reverse-transcriptase polymerase chain reaction (C Q RT-PCR) assay is characterized and used to analyze levels of NGF mRNA in cultured VSMCs derived from the SHR and WKY strains as well as bladder tissue. Differences in NGF secretion rates between SHR and WKY VSMCs were partially due to an increased stability of NGF mRNA in SHR VSMCs. Following treatment with platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta 1) to elevate NGF production, the half-life of the NGF mRNA was 104.5 +/- 18.0 min in SHR VSMCs, compared to only 36.5 +/- 11.6 min in WKY VSMCs. Sequence analysis of the 3' untranslated region (UTR) revealed no strain differences in cis-acting sequences potentially involved in determining mRNA stability. Thus, it seems unlikely to be a 3'UTR mutation that prolongs mRNA lifetime. Rather, differential regulation of an RNA-binding protein may play a role in the abnormal NGF mRNA stability in SHR VSMCs. SHR VSMCs also demonstrate an increased translational efficiency of NGF protein; more NGF protein is synthesized per unit of NGF mRNA. The use of a C Q RT-PCR assay has allowed the determination that abnormal NGF mRNA stabilization as well as altered translational efficiency may contribute to excess NGF synthesis and progressive hypertension in the SHR.

The production of nerve growth factor (NGF) in peripheral organs may play a role in the pathophysiology of hypertension and in obstructive disorders of the bladder outlet. We have been examining the cellular processes of NGF delivery and secretion in smooth muscle. NGF secretion from vascular smooth muscle cells (VSMCs) cultured from genetically hypertensive (WKHT), hyperactive (WKHA), and a control Wistar rat strain were assayed using a two-site ELISA of the culture media. Bladder smooth muscle cells (BSMCs) from the Wistar strain were also studied. The serine protease, thrombin, increased NGF secretion from all types of VSMCs but had no effect on Wistar BSMCs. The thrombin-mediated increase in NGF secretion was prevented by actinomycin D and cycloheximide, suggesting that RNA transcription and protein synthesis are required. The effect of thrombin was additive with a phorbol ester-induced elevation in NGF secretion rates from 4 to 6 h and was attenuated by a 24-h downregulation of protein kinase C. These results suggest that extracellular protease activity may regulate NGF secretion in smooth muscle. Thrombin may act in response to vascular injury, increasing NGF secretion from VSMCs, initiating VSMC migration, and preparing the VSMCs for reinnervation following an insult.

Expression of c-erbA genes, which encode thyroid hormone receptors, has been shown to be tissue and age specific. The differential regulation of thyroid hormone receptor mRNAs in rat brain was examined in the present study using Northern hybridization techniques. Ontogenic profiles of two known mRNAs for rat thyroid hormone receptors (rTR), rTR alpha and rTR beta, were determined in the rat cerebellum and cerebral cortex. Three bands of approximately 6, 5 and 2.6 kb in size were detected at 1, 6, 12 and 21 days of age (preweanling period) and in the adult, in both brain regions using a rTR alpha-common DNA probe. The 2.6-kb band was expressed at much higher levels than either the 5- or 6-kb band at all ages tested. The 6- and 5-kb bands were expressed at similar levels throughout the preweanling period in the cerebellum, but only at 1 and 6 days of age in the cerebral cortex. The 6-kb transcript was expressed at a much lower level than the 5-kb mRNA by postnatal day 12 in the cerebral cortex. A similar change in the relative level of 6- to 5-kb mRNA expression was noted in cerebellar mRNA isolated from adult animals. The overall expression of rTR alpha mRNA was less in the adult cerebellum and cerebral cortex compared to that in the preweanling period. The rTR beta transcripts were present in very low levels in the cerebral cortex and were undetectable in the cerebellum. These results are consistent with the fact that the developing brain is more sensitive to thyroid hormone than the mature rat brain.(ABSTRACT TRUNCATED AT 250 WORDS)

In risk assessments the various forms of iodine have been treated as if they were toxicologically equivalent. While iodide (I-) and iodate (IO3-) have been studied, no studies concerned with the subchronic toxicity of iodine (I2) have been conducted in experimental animals. This study examined toxicities associated with iodine. Rats were treated with 0, 1, 3, 10, and 100 mg/l of either iodine or iodide (as Nal) in the drinking water for 100 d. Treatment had no effect on body, brain, or heart weights in either sex, or on testes weights in male rats. Although differences in kidney and liver weights were noted, they did not appear to be treatment related. Thyroid weight in male rats was significantly increased with an increasing concentration of iodide in the water, but not iodine. In contrast, thyroid weight decreased at the highest dose of iodide in female rats. Hematocrit, hemoglobin, and blood urea nitrogen (BUN) values were relatively constant and did not vary with treatment. There were no significant differences in AST, ALT, cholesterol, and triglyceride values. After 10 d on treatment a dose-related trend in increased plasma T4 concentrations was observed in both sexes treated with iodine. Statistically significant increases in the T4/T3 ratio in both sexes was also noted with iodine treatment. This increase was maintained for 100 d of treatment. Iodide did not produce this effect at 10 d. Although there was a significant increase in T4/T3 ratios in female rats after 100 d of treatment with iodide, the magnitude of the changes was smaller than that observed with iodine treatments. The results of this study indicate that iodine and iodide affect thyroid hormone status in substantially different ways.

The alcoholism literature abounds with reports of the alcoholic personality and alcoholic subtypes. However, very minimal research on the relationship between the subtypes and treatment procedures is available. With the power of computer technology now accessible so readily, it is possible to apply sophisticated statistical methods to determine the extent of the association. The present paper describes the development of an automatic referral system (Autorf) on an inpatient alcohol and day unit (N = 150). More importantly, preliminary results with regard to the validity of the Autorf system are reported. Implications for treatment of alcoholics and program efficiency are discussed.