المؤلفون: Tamaoki, Naritaka, Siebert, Stefan, Maeda, Takuya, Ha, Ngoc-Han, Good, Meghan L., Huang, Yin, Vodnala, Suman K., Haro-Mora, Juan J., Uchida, Naoya, Tisdale, John F., Sweeney, Colin L., Choi, Uimook, Brault, Julie, Koontz, Sherry, Malech, Harry L., Yamazaki, Yasuhiro, Isonaka, Risa, Goldstein, David S., Kimura, Masaki, Takebe, Takanori, Zou, Jizhong, Stroncek, David F., Robey, Pamela G., Kruhlak, Michael J., Restifo, Nicholas P., Vizcardo, Raul

المصدر: Cell Reports Methods ; volume 3, issue 4, page 100460 ; ISSN 2667-2375

مصطلحات موضوعية: Computer Science Applications, Radiology, Nuclear Medicine and imaging, Genetics, Biochemistry, Genetics and Molecular Biology (miscellaneous), Biochemistry, Biotechnology

الإتاحة: https://doi.org/10.1016/j.crmeth.2023.100460Test
https://api.elsevier.com/content/article/PII:S2667237523000796?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2667237523000796?httpAccept=text/plainTest

المؤلفون: Isonaka, Risa, Sullivan, Patti, Goldstein, David S.

المساهمون: National Institute of Neurological Disorders and Stroke, National Institutes of Health

المصدر: Translational Neurodegeneration ; volume 11, issue 1 ; ISSN 2047-9158

مصطلحات موضوعية: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Neurology (clinical)

الوصف: Background Parkinson’s disease (PD) is characterized by intra-neuronal deposition of the protein α-synuclein (α-syn) and by deficiencies of the catecholamines dopamine and norepinephrine (NE) in the brain and heart. Accumulation of α-syn in sympathetic noradrenergic nerves may provide a useful PD biomarker; however, whether α-syn buildup is pathophysiological has been unclear. If it were, one would expect associations of intra-neuronal α-syn deposition with catecholaminergic denervation and with decreased NE contents in the same samples. Methods We assayed immunoreactive α-syn and tyrosine hydroxylase (TH, a marker of catecholaminergic innervation) concurrently with catecholamines in coded post-mortem scalp skin, submandibular gland (SMG), and apical left ventricular myocardial tissue samples from 14 patients with autopsy-proven PD and 12 age-matched control subjects who did not have a neurodegenerative disease. Results The PD group had increased α-syn in sympathetic noradrenergically innervated arrector pili muscles (5.7 times control, P < 0.0001), SMG (35 times control, P = 0.0011), and myocardium (11 times control, P = 0.0011). Myocardial TH in the PD group was decreased by 65% compared to the control group ( P = 0.0008), whereas the groups did not differ in TH in either arrector pili muscles or SMG. Similarly, myocardial NE was decreased by 92% in the PD group ( P < 0.0001), but the groups did not differ in NE in either scalp skin or SMG. Conclusions PD entails increased α-syn in skin, SMG, and myocardial tissues. In skin and SMG, augmented α-syn deposition in sympathetic nerves does not seem to be pathogenic. The pathophysiological significance of intra-neuronal α-syn deposition appears to be organ-selective and prominent in the heart.

الإتاحة: https://doi.org/10.1186/s40035-022-00289-yTest

المؤلفون: Lenka, Abhishek^1,2 (AUTHOR), Isonaka, Risa¹ (AUTHOR), Holmes, Courtney¹ (AUTHOR), Goldstein, David S.¹ (AUTHOR) goldsteind@ninds.nih.gov

المصدر: Clinical Autonomic Research. Dec2023, Vol. 33 Issue 6, p737-747. 11p.

مصطلحات موضوعية: *POSITRON emission tomography, *MULTIPLE system atrophy, *LEWY body dementia, *PARKINSON'S disease, *ORTHOSTATIC hypotension

الشركة/الكيان: NATIONAL Institutes of Health (U.S.)

مستخلص: Purpose: Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), no known secondary cause, and lack of a neurodegenerative movement or cognitive disorder. Clinically diagnosed PAF can evolve ("phenoconvert") to a central Lewy body disease [LBD, e.g., Parkinson's disease (PD) or dementia with Lewy bodies (DLB)] or to the non-LBD synucleinopathy multiple system atrophy (MSA). Since cardiac 18F-dopamine-derived radioactivity usually is low in LBDs and usually is normal in MSA, we hypothesized that patients with PAF with low cardiac 18F-dopamine-derived radioactivity would be more likely to phenoconvert to a central LBD than to MSA. Methods: We reviewed data from all the patients seen at the National Institutes of Health Clinical Center from 1994 to 2023 with a clinical diagnosis of PAF and data about 18F-dopamine positron emission tomography (PET). Results: Nineteen patients (15 with low 18F-dopamine-derived radioactivity, 4 with normal radioactivity) met the above criteria and had follow-up data. Nine (47%) phenoconverted to a central synucleinopathy over a mean of 6.6 years (range 1.5–18.8 years). All 6 patients with low cardiac 18F-dopamine-derived radioactivity who phenoconverted during follow-up developed a central LBD, whereas none of 4 patients with consistently normal 18F-dopamine PET phenoconverted to a central LBD (p = 0.0048), 3 evolving to probable MSA and 1 upon autopsy having neither a LBD nor MSA. Conclusion: Cardiac 18F-dopamine PET can predict the type of phenoconversion of PAF. This capability could refine eligibility criteria for entry into disease-modification trials aimed at preventing evolution of PAF to symptomatic central LBDs. [ABSTRACT FROM AUTHOR]

المؤلفون: Goldstein, David S., Isonaka, Risa, Holmes, Courtney, Ding, Yu‐Shin, Sharabi, Yehonatan

المساهمون: Division or Intramural Research, NINDS, NIH

المصدر: Annals of Clinical and Translational Neurology ; volume 7, issue 10, page 1908-1918 ; ISSN 2328-9503 2328-9503

الوصف: Objective Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), absence of signs of central neurodegeneration, and profound deficiency of the sympathetic neurotransmitter norepinephrine. Reports have disagreed about mechanisms of the noradrenergic lesion. Neuropathological studies have highlighted denervation, while functional studies have emphasized deficient vesicular sequestration of cytoplasmic catecholamines in extant neurons. We examined both aspects by a combined positron emission tomographic (PET) neuroimaging approach using 11 C‐methylreboxetine ( 11 C‐MRB), a selective ligand for the cell membrane norepinephrine transporter, to quantify interventricular septal myocardial noradrenergic innervation and using 18 F‐dopamine ( 18 F‐DA) to assess intraneuronal vesicular storage in the same subjects. Methods Seven comprehensively tested PAF patients and 11 controls underwent 11 C‐MRB PET scanning for 45 minutes (dynamic 5X1’, 3X5’, 1X10’, static 15 minutes) and 18 F‐DA scanning for 30 minutes (same dynamic imaging sequence) after 3‐minute infusions of the tracers on separate days. Results In the PAF group septal 11 C‐MRB‐derived radioactivity in the static frame was decreased by 26.7% from control (p = 0.012). After adjustment for nonspecific binding of 11 C‐MRB, the PAF group had a 41.1% mean decrease in myocardial 11 C‐MRB‐derived radioactivity (p = 0.015). The PAF patients had five times faster postinfusion loss of 18 F‐DA‐derived radioactivity (70 ± 3% vs. 14 ± 8% by 30 minutes, p < 0.0001). At all time points after infusion of 18 F‐DA and 11 C‐MRB mean 18 F/ 11 C ratios in septal myocardium were lower in the PAF than control group. Interpretation PAF entails moderately decreased cardiac sympathetic innervation and a substantial vesicular storage defect in residual nerves.

الإتاحة: https://doi.org/10.1002/acn3.51184Test

المؤلفون: Lenka, Abhishek, Isonaka, Risa, Holmes, Courtney, Goldstein, David S.

المساهمون: National Institute of Neurological Disorders and Stroke

المصدر: Clinical Autonomic Research ; volume 33, issue 6, page 737-747 ; ISSN 0959-9851 1619-1560

مصطلحات موضوعية: Neurology (clinical), Endocrine and Autonomic Systems

الإتاحة: https://doi.org/10.1007/s10286-023-00987-1Test

المؤلفون: Isonaka, Risa, Rosenberg, Avi Z., Sullivan, Patti, Corrales, Abraham, Holmes, Courtney, Sharabi, Yehonatan, Goldstein, David S.

المصدر: Hypertension ; volume 73, issue 4, page 910-918 ; ISSN 0194-911X 1524-4563

الوصف: Lewy body diseases involve neurogenic orthostatic hypotension (nOH), cardiac noradrenergic deficiency, and deposition of the protein AS (alpha-synuclein) in sympathetic ganglion tissue. Mechanisms linking these abnormalities are poorly understood. One link may be AS deposition within sympathetic neurons. We validated methodology to quantify AS colocalization with TH (tyrosine hydroxylase), a marker of sympathetic noradrenergic innervation, and assessed associations of AS/TH colocalization with myocardial norepinephrine content and cardiac sympathetic neuroimaging data in nOH. Postmortem sympathetic ganglionic AS/TH colocalization indices and myocardial norepinephrine contents were measured in 4 Lewy body and 3 rare non-Lewy body nOH patients. Sixteen Lewy body and 11 non-Lewy body nOH patients underwent in vivo skin biopsies and thoracic 18 F-dopamine positron emission tomographic scanning, with cutaneous colocalization indices expressed versus cardiac 18 F-dopamine–derived radioactivity. Ganglionic AS/TH colocalization indices were higher and myocardial norepinephrine lower in Lewy body than non-Lewy body nOH ( P =0.0020, P =0.014). The Lewy body nOH group had higher AS/TH colocalization indices in skin biopsies and lower myocardial 18 F-dopamine–derived radioactivity than did the non-Lewy body nOH group ( P <0.0001 each). All Lewy body nOH patients had colocalization indices >1.5 in skin biopsies and 18 F-dopamine–derived radioactivity <6000 nCi-kg/cc-mCi, a combination not seen in non-Lewy body nOH patients ( P <0.0001). In Lewy body nOH, AS deposition in sympathetic noradrenergic nerves is related to postmortem neurochemical and in vivo neuroimaging evidence of myocardial noradrenergic deficiency. These associations raise the possibility that intraneuronal AS deposition plays a pathophysiological role in the myocardial sympathetic neurodegeneration attending Lewy body nOH.

الإتاحة: https://doi.org/10.1161/hypertensionaha.118.12642Test

المؤلفون: Isonaka, Risa, Katakura, Takashi, Kawakami, Tadashi

المصدر: Clinical Research and Trials ; volume 4, issue 5 ; ISSN 2059-0377

الإتاحة: https://doi.org/10.15761/crt.1000233Test

المؤلفون: Goldstein, David S., Pekker, Mark J., Sullivan, Patti, Isonaka, Risa, Sharabi, Yehonatan

المصدر: Journal of the American Heart Association ; volume 11, issue 11 ; ISSN 2047-9980

الوصف: Background Lewy body diseases (LBDs) feature deficiency of the sympathetic neurotransmitter norepinephrine in the left ventricular myocardium and sympathetic intra‐neuronal deposition of the protein alpha‐synuclein (αS). LBDs therefore are autonomic synucleinopathies. Computational modeling has revealed multiple functional abnormalities in residual myocardial sympathetic noradrenergic nerves in LBDs, including decreased norepinephrine synthesis, vesicular storage, and recycling. We report an extended model that enables predictions about the progression of LBDs and effects of genetic predispositions and treatments on that progression. Methods and Results The model combines cardiac sympathetic activation with autotoxicity mediated by the dopamine metabolite 3,4‐dihydroxyphenylacetaldehyde. We tested the model by its ability to predict longitudinal empirical data based on cardiac sympathetic neuroimaging, effects of genetic variations related to particular intra‐neuronal reactions, treatment by monoamine oxidase inhibition to decrease 3,4‐dihydroxyphenylacetaldehyde production, and post‐mortem myocardial tissue contents of catecholamines and αS. The new model generated a triphasic decline in myocardial norepinephrine content. This pattern was confirmed by empirical data from serial cardiac 18 F‐dopamine positron emission tomographic scanning in patients with LBDs. The model also correctly predicted empirical data about effects of genetic variants and monoamine oxidase inhibition and about myocardial levels of catecholamines and αS. Conclusions The present computational model predicts a triphasic decline in myocardial norepinephrine content as LBDs progress. According to the model, disease‐modifying interventions begun at the transition from the first to the second phase delay the onset of symptomatic disease. Computational modeling coupled with biomarkers of preclinical autonomic synucleinopathy may enable early detection and more effective treatment of LBDs.

الإتاحة: https://doi.org/10.1161/jaha.121.024411Test

المؤلفون: Hosono, Kanako, Isonaka, Risa, Kawakami, Tadashi, Narumiya, Shuh, Majima, Masataka

المساهمون: 成宮, 周

الوصف: Lymphangiogenesis plays an important role in homeostasis, metabolism, and immunity, and also occurs during wound-healing. Here, we examined the roles of prostaglandin E2 (PGE2) receptor (EP) signaling in enhancement of lymphangiogenesis in wound healing processes. The hole-punch was made in the ears of male C57BL/6 mice using a metal ear punch. Healing process and lymphangiogenesis together with macrophage recruitment were analyzed in EP knockout mice. Lymphangiogenesis was up-regulated in the granulation tissues at the margins of punched-hole wounds in mouse ears, and this increase was accompanied by increased expression levels of COX-2 and microsomal prostaglandin E synthase-1. Administration of celecoxib, a COX-2 inhibitor, suppressed lymphangiogenesis in the granulation tissues and reduced the induction of the pro-lymphangiogenic factors, vascular endothelial growth factor (VEGF) -C and VEGF-D. Topical applications of selective EP receptor agonists enhanced the expressions of lymphatic vessel endothelial hyaluronan receptor-1 and VEGF receptor-3. The wound-healing processes and recruitment of CD11b-positive macrophages, which produced VEGF-C and VEGF-D, were suppressed under COX-2 inhibition. Mice lacking either EP3 or EP4 exhibited reduced wound-healing, lymphangiogenesis and recruitment of M2 macrophages, compared with wild type mice. Proliferation of cultured human lymphatic endothelial cells was not detected under PGE2 stimulation. Lymphangiogenesis and recruitment of M2 macrophages that produced VEGF-C/D were suppressed in mice treated with a COX-2 inhibitor or lacking either EP3 or EP4 during wound healing. COX-2 and EP3/EP4 signaling may be novel targets to control lymphangiogenesis in vivo.

وصف الملف: application/pdf

العلاقة: http://hdl.handle.net/2433/218619Test; PLOS ONE; 11; 10; e0162532

الإتاحة: http://hdl.handle.net/2433/218619Test

المؤلفون: Isonaka, Risa (AUTHOR), Sullivan, Patti (AUTHOR), Holmes, Courtney (AUTHOR), Goldstein, David S.¹ (AUTHOR) goldsteind@ninds.nih.gov

المصدر: Clinical Autonomic Research. Jun2024, p1-11.

مستخلص: Purpose: Neurogenic orthostatic hypotension (nOH) results from deficient reflexive delivery of norepinephrine to cardiovascular receptors in response to decreased cardiac venous return. Lewy body (LB) forms of nOH are characterized by low 18F-dopamine-derived radioactivity (a measure of cardiac noradrenergic deficiency), olfactory dysfunction by the University of Pennsylvania Smell Identification Test (UPSIT), and increased deposition of alpha-synuclein (α-syn) in dermal sympathetic noradrenergic nerves by the α-syn-tyrosine hydroxylase (TH) colocalization index. This observational, cross-sectional study explored whether combinations of these biomarkers specifically identify LB forms of nOH.Clinical laboratory data were reviewed from patients referred for evaluation at the National Institutes of Health for chronic autonomic failure between 2011 and 2023. The cutoff value for low myocardial 18F-dopamine-derived radioactivity was 6000 nCi-kg/cc-mCi, for olfactory dysfunction an UPSIT score ≤ 28, and for an increased α-syn-TH colocalization index ≥ 1.57.A total of 44 patients (31 LB, 13 non-LB nOH) had data for all three biomarkers. Compared to the non-LB group, the LB nOH group had low myocardial 18F-dopamine-derived radioactivity, low UPSIT scores, and high α-syn-TH colocalization indexes (p < 0.0001 each). Combining the three biomarkers completely separated the groups. Cluster analysis identified two distinct groups (p < 0.0001) independently of the clinical diagnosis, with one cluster corresponding exactly to LB nOH.LB forms of nOH feature cardiac noradrenergic deficiency, olfactory dysfunction, and increased α-syn-TH colocalization in skin biopsies. Combining the data for these variables efficiently separates LB from non-LB nOH. Independently of the clinical diagnosis, this biomarker triad identifies a pathophysiologically distinct cluster of nOH patients.Methods: Neurogenic orthostatic hypotension (nOH) results from deficient reflexive delivery of norepinephrine to cardiovascular receptors in response to decreased cardiac venous return. Lewy body (LB) forms of nOH are characterized by low 18F-dopamine-derived radioactivity (a measure of cardiac noradrenergic deficiency), olfactory dysfunction by the University of Pennsylvania Smell Identification Test (UPSIT), and increased deposition of alpha-synuclein (α-syn) in dermal sympathetic noradrenergic nerves by the α-syn-tyrosine hydroxylase (TH) colocalization index. This observational, cross-sectional study explored whether combinations of these biomarkers specifically identify LB forms of nOH.Clinical laboratory data were reviewed from patients referred for evaluation at the National Institutes of Health for chronic autonomic failure between 2011 and 2023. The cutoff value for low myocardial 18F-dopamine-derived radioactivity was 6000 nCi-kg/cc-mCi, for olfactory dysfunction an UPSIT score ≤ 28, and for an increased α-syn-TH colocalization index ≥ 1.57.A total of 44 patients (31 LB, 13 non-LB nOH) had data for all three biomarkers. Compared to the non-LB group, the LB nOH group had low myocardial 18F-dopamine-derived radioactivity, low UPSIT scores, and high α-syn-TH colocalization indexes (p < 0.0001 each). Combining the three biomarkers completely separated the groups. Cluster analysis identified two distinct groups (p < 0.0001) independently of the clinical diagnosis, with one cluster corresponding exactly to LB nOH.LB forms of nOH feature cardiac noradrenergic deficiency, olfactory dysfunction, and increased α-syn-TH colocalization in skin biopsies. Combining the data for these variables efficiently separates LB from non-LB nOH. Independently of the clinical diagnosis, this biomarker triad identifies a pathophysiologically distinct cluster of nOH patients.Results: Neurogenic orthostatic hypotension (nOH) results from deficient reflexive delivery of norepinephrine to cardiovascular receptors in response to decreased cardiac venous return. Lewy body (LB) forms of nOH are characterized by low 18F-dopamine-derived radioactivity (a measure of cardiac noradrenergic deficiency), olfactory dysfunction by the University of Pennsylvania Smell Identification Test (UPSIT), and increased deposition of alpha-synuclein (α-syn) in dermal sympathetic noradrenergic nerves by the α-syn-tyrosine hydroxylase (TH) colocalization index. This observational, cross-sectional study explored whether combinations of these biomarkers specifically identify LB forms of nOH.Clinical laboratory data were reviewed from patients referred for evaluation at the National Institutes of Health for chronic autonomic failure between 2011 and 2023. The cutoff value for low myocardial 18F-dopamine-derived radioactivity was 6000 nCi-kg/cc-mCi, for olfactory dysfunction an UPSIT score ≤ 28, and for an increased α-syn-TH colocalization index ≥ 1.57.A total of 44 patients (31 LB, 13 non-LB nOH) had data for all three biomarkers. Compared to the non-LB group, the LB nOH group had low myocardial 18F-dopamine-derived radioactivity, low UPSIT scores, and high α-syn-TH colocalization indexes (p < 0.0001 each). Combining the three biomarkers completely separated the groups. Cluster analysis identified two distinct groups (p < 0.0001) independently of the clinical diagnosis, with one cluster corresponding exactly to LB nOH.LB forms of nOH feature cardiac noradrenergic deficiency, olfactory dysfunction, and increased α-syn-TH colocalization in skin biopsies. Combining the data for these variables efficiently separates LB from non-LB nOH. Independently of the clinical diagnosis, this biomarker triad identifies a pathophysiologically distinct cluster of nOH patients.Conclusion: Neurogenic orthostatic hypotension (nOH) results from deficient reflexive delivery of norepinephrine to cardiovascular receptors in response to decreased cardiac venous return. Lewy body (LB) forms of nOH are characterized by low 18F-dopamine-derived radioactivity (a measure of cardiac noradrenergic deficiency), olfactory dysfunction by the University of Pennsylvania Smell Identification Test (UPSIT), and increased deposition of alpha-synuclein (α-syn) in dermal sympathetic noradrenergic nerves by the α-syn-tyrosine hydroxylase (TH) colocalization index. This observational, cross-sectional study explored whether combinations of these biomarkers specifically identify LB forms of nOH.Clinical laboratory data were reviewed from patients referred for evaluation at the National Institutes of Health for chronic autonomic failure between 2011 and 2023. The cutoff value for low myocardial 18F-dopamine-derived radioactivity was 6000 nCi-kg/cc-mCi, for olfactory dysfunction an UPSIT score ≤ 28, and for an increased α-syn-TH colocalization index ≥ 1.57.A total of 44 patients (31 LB, 13 non-LB nOH) had data for all three biomarkers. Compared to the non-LB group, the LB nOH group had low myocardial 18F-dopamine-derived radioactivity, low UPSIT scores, and high α-syn-TH colocalization indexes (p < 0.0001 each). Combining the three biomarkers completely separated the groups. Cluster analysis identified two distinct groups (p < 0.0001) independently of the clinical diagnosis, with one cluster corresponding exactly to LB nOH.LB forms of nOH feature cardiac noradrenergic deficiency, olfactory dysfunction, and increased α-syn-TH colocalization in skin biopsies. Combining the data for these variables efficiently separates LB from non-LB nOH. Independently of the clinical diagnosis, this biomarker triad identifies a pathophysiologically distinct cluster of nOH patients. [ABSTRACT FROM AUTHOR]