#METABOLOMICS WORKBENCH Codreags00_20230112_121230 DATATRACK_ID:3689 STUDY_ID:ST002442 ANALYSIS_ID:AN003979 PROJECT_ID:PR001573 VERSION 1 CREATED_ON January 13, 2023, 8:05 am #PROJECT PR:PROJECT_TITLE Alterations in CSF Urea Occur in Late Manifest Stage Huntington Disease PR:PROJECT_TYPE Untargeted Metabolomics analysis PR:PROJECT_SUMMARY Huntington Disease (HD) is a neurodegenerative disorder caused by expanded PR:PROJECT_SUMMARY cytosine-adenine-guanine (CAG) repeats in the Huntingtin gene, resulting in the PR:PROJECT_SUMMARY production of mutant huntingtin proteins (mHTT). Previous research has PR:PROJECT_SUMMARY identified urea as a key metabolite elevated in HD animal models and post-mortem PR:PROJECT_SUMMARY tissues of HD patients. The exact timing of these elevations in urea and the PR:PROJECT_SUMMARY molecular mechanism(s) responsible for these disturbances remain unknown. To PR:PROJECT_SUMMARY better understand the pathophysiologic mechanisms responsible for elevations in PR:PROJECT_SUMMARY urea in HD, we completed a global metabolomic profile of cerebrospinal fluid PR:PROJECT_SUMMARY (CSF) from individuals who were at several stages of disease: pre-manifest PR:PROJECT_SUMMARY (PRE), manifest (MAN), and late-manifest (LATE) HD participants compared to PR:PROJECT_SUMMARY controls. We found approximately 500 metabolites were significantly altered in PR:PROJECT_SUMMARY pre-manifest participants compared to controls, although no significant PR:PROJECT_SUMMARY difference in CSF urea or urea metabolites. Interestingly, CSF urea was only PR:PROJECT_SUMMARY significantly elevated in LATE participants compared to controls. There were no PR:PROJECT_SUMMARY changes in the urea metabolites, citrulline, ornithine and arginine throughout PR:PROJECT_SUMMARY disease; however, we did observe changes in acetate, creatinine, PR:PROJECT_SUMMARY 4-acetamidobutanoate and 4-aminobutyraldehyde which are indirect modifiers of PR:PROJECT_SUMMARY urea. Overall, our study confirms that elevations in urea do occur in HD, albeit PR:PROJECT_SUMMARY later in disease and that these changes may reflect more central impairments to PR:PROJECT_SUMMARY cellular energy metabolism yet to be explored. PR:INSTITUTE Vanderbilt University PR:DEPARTMENT Chemistry PR:LABORATORY Center for Innovative Technology PR:LAST_NAME CODREANU PR:FIRST_NAME SIMONA PR:ADDRESS 1234 STEVENSON CENTER LANE PR:EMAIL SIMONA.CODREANU@VANDERBILT.EDU PR:PHONE 6158758422 #STUDY ST:STUDY_TITLE Alterations in CSF Urea Occur in Late Manifest Stage Huntington Disease ST:STUDY_TYPE untargeted metabolomics analysis ST:STUDY_SUMMARY Huntington Disease (HD) is a neurodegenerative disorder caused by expanded ST:STUDY_SUMMARY cytosine-adenine-guanine (CAG) repeats in the Huntingtin gene, resulting in the ST:STUDY_SUMMARY production of mutant huntingtin proteins (mHTT). Previous research has ST:STUDY_SUMMARY identified urea as a key metabolite elevated in HD animal models and post-mortem ST:STUDY_SUMMARY tissues of HD patients. The exact timing of these elevations in urea and the ST:STUDY_SUMMARY molecular mechanism(s) responsible for these disturbances remain unknown. To ST:STUDY_SUMMARY better understand the pathophysiologic mechanisms responsible for elevations in ST:STUDY_SUMMARY urea in HD, we completed a global metabolomic profile of cerebrospinal fluid ST:STUDY_SUMMARY (CSF) from individuals who were at several stages of disease: pre-manifest ST:STUDY_SUMMARY (PRE), manifest (MAN), and late-manifest (LATE) HD participants compared to ST:STUDY_SUMMARY controls. We found approximately 500 metabolites were significantly altered in ST:STUDY_SUMMARY pre-manifest participants compared to controls, although no significant ST:STUDY_SUMMARY difference in CSF urea or urea metabolites. Interestingly, CSF urea was only ST:STUDY_SUMMARY significantly elevated in LATE participants compared to controls. There were no ST:STUDY_SUMMARY changes in the urea metabolites, citrulline, ornithine and arginine throughout ST:STUDY_SUMMARY disease; however, we did observe changes in acetate, creatinine, ST:STUDY_SUMMARY 4-acetamidobutanoate and 4-aminobutyraldehyde which are indirect modifiers of ST:STUDY_SUMMARY urea. Overall, our study confirms that elevations in urea do occur in HD, albeit ST:STUDY_SUMMARY later in disease and that these changes may reflect more central impairments to ST:STUDY_SUMMARY cellular energy metabolism yet to be explored. ST:INSTITUTE Vanderbilt University ST:DEPARTMENT Chemistry ST:LABORATORY Center for Innovative Technology ST:LAST_NAME CODREANU ST:FIRST_NAME SIMONA ST:ADDRESS 1234 STEVENSON CENTER LANE ST:EMAIL SIMONA.CODREANU@VANDERBILT.EDU ST:PHONE 6158758422 ST:NUM_GROUPS 4 ST:TOTAL_SUBJECTS 60 #SUBJECT SU:SUBJECT_TYPE Human SU:SUBJECT_SPECIES Homo sapiens SU:TAXONOMY_ID 9606 SU:GENDER Male and female #SUBJECT_SAMPLE_FACTORS: SUBJECT(optional)[tab]SAMPLE[tab]FACTORS(NAME:VALUE pairs separated by |)[tab]Raw file names and additional sample data SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_C07_C_1_1 Genotype:CONTROL | sex:m | age:32 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_C07_C_1_1 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_D01_C_1_1 Genotype:CONTROL | sex:m | age:28 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_D01_C_1_1 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_D02_C_1_1 Genotype:CONTROL | sex:m | age:44 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_D02_C_1_1 SUBJECT_SAMPLE_FACTORS - 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SC_20201109_HILICp_FMS_CSF_A06_HD_4 Genotype:LATE MANIFEST | sex:m | age:58 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_A06_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_A09_HD_4 Genotype:LATE MANIFEST | sex:m | age:66 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_A09_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_A10_HD_4 Genotype:LATE MANIFEST | sex:m | age:46 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_A10_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_A11_HD_4 Genotype:LATE MANIFEST | sex:m | age:60 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_A11_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_B01_HD_4 Genotype:LATE MANIFEST | sex:f | age:58 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_B01_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_B11_HD_4 Genotype:LATE MANIFEST | sex:f | age:65 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_B11_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_C02_HD_4 Genotype:LATE MANIFEST | sex:f | age:47 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_C02_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_C03_HD_4 Genotype:LATE MANIFEST | sex:f | age:57 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_C03_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_C06_HD_4 Genotype:LATE MANIFEST | sex:f | age:55 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_C06_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_D03_HD_4 Genotype:LATE MANIFEST | sex:m | age:51 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_D03_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_D04_HD_4 Genotype:LATE MANIFEST | sex:m | age:47 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_D04_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_D07_HD_4 Genotype:LATE MANIFEST | sex:m | age:69 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_D07_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_E07_HD_4 Genotype:LATE MANIFEST | sex:m | age:63 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_E07_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_E09_HD_4 Genotype:LATE MANIFEST | sex:f | age:72 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_E09_HD_4 SUBJECT_SAMPLE_FACTORS - SC_20201109_HILICp_FMS_CSF_F08_HD_4 Genotype:LATE MANIFEST | sex:m | age:60 RAW_FILE_NAME=SC_20201109_HILICp_FMS_CSF_F08_HD_4 #COLLECTION CO:COLLECTION_SUMMARY CSF samples were collected from 60 participants as part of the CHDI HD-Clarity CO:COLLECTION_SUMMARY study. There were 16 PRE, 16 MAN, 16 LATE HD participants and 12 control CO:COLLECTION_SUMMARY participants. Disease stage was determined using the diagnostic confidence level CO:COLLECTION_SUMMARY (DCL), length of CAG expansion and burden of pathology calculated from (CAG CO:COLLECTION_SUMMARY expansion – 35.5) x Age. Control participants were individuals without a known CO:COLLECTION_SUMMARY history of Huntington Disease (HD). All HD participants have a CAG expansion of CO:COLLECTION_SUMMARY > 40. PRE participants were not motor manifest as indicated by a DCL of <4 and a CO:COLLECTION_SUMMARY burden of pathology of > 250. MAN participants had a DCL =4 and a total CO:COLLECTION_SUMMARY functional capacity (TFC) between 7-13. The LATE group had all the above CO:COLLECTION_SUMMARY criteria for MAN and a TFC score between 0-6. Repeat CSF and blood samples CO:COLLECTION_SUMMARY collected 4-8 weeks after a baseline (BL) visit are provided for all control and CO:COLLECTION_SUMMARY PRE participants. Participants’ age and gender are reported here. Three CO:COLLECTION_SUMMARY participants (2 PRE, 1 MAN) were taking supplemental vitamins; however, their CO:COLLECTION_SUMMARY metal levels were similar to those in their corresponding participant group and CO:COLLECTION_SUMMARY thus, the data from these participants are included. Basic demographics like age CO:COLLECTION_SUMMARY and gender were reported previously in addition to participants' scores on a CO:COLLECTION_SUMMARY battery of cognitive, behavioral and motor assessments including the symbol CO:COLLECTION_SUMMARY digit modality test (SDMT), Stroop Word Reading (SWR), total functional capacity CO:COLLECTION_SUMMARY (TFC), total motor score (TMS) and the recently developed cUHDRS. CO:SAMPLE_TYPE CSF CO:STORAGE_CONDITIONS -80℃ #TREATMENT TR:TREATMENT_SUMMARY No treatment #SAMPLEPREP SP:SAMPLEPREP_SUMMARY CSF samples collected were flash frozen and stored at -80°C until analyzed via SP:SAMPLEPREP_SUMMARY Liquid ChromatographyHigh Resolution Mass Spectrometry (LC-HRMS and SP:SAMPLEPREP_SUMMARY LC-HRMS/MS)-based metabolomics in the Vanderbilt Center for Innovative SP:SAMPLEPREP_SUMMARY Technology (CIT) using previously described methods (cite). Briefly, equal SP:SAMPLEPREP_SUMMARY volumes (100 µL) of previously frozen CSF was diluted with 100 µL ice-cold SP:SAMPLEPREP_SUMMARY lysis buffer (1:1:2, Acetonitrile:MeOH:Ammonium Bicarbonate 0.1M, pH 8.0, LC-MS SP:SAMPLEPREP_SUMMARY grade). Addition of isotopically labeled phenylalanine-D8 and biotin-D2 were SP:SAMPLEPREP_SUMMARY added to individual samples prior to protein precipitation by addition of 800 SP:SAMPLEPREP_SUMMARY µL of ice-cold methanol. Following overnight incubation at -80°C, precipitated SP:SAMPLEPREP_SUMMARY proteins were pelleted by centrifugation at 10,000 rpm for 10 min and metabolite SP:SAMPLEPREP_SUMMARY extracts were dried down in vacuo and stored at -80°C until reconstitution SP:SAMPLEPREP_SUMMARY prior to MS analysis. #CHROMATOGRAPHY CH:CHROMATOGRAPHY_SUMMARY CSF extracts (5uL injection volume) were separated on an ACQUITY UPLC BEH Amide CH:CHROMATOGRAPHY_SUMMARY HILIC 1.7μm, 2.1 × 100 mm column (Waters Corporation, Milford, MA) held at CH:CHROMATOGRAPHY_SUMMARY 30°C as previously described (cite). Briefly, liquid chromatography was CH:CHROMATOGRAPHY_SUMMARY performed at 200 µL min−1 using solvent A (5 mM ammonium formate in 90% CH:CHROMATOGRAPHY_SUMMARY water, 10% acetonitrile and 0.1% formic acid) and solvent B (5 mM ammonium CH:CHROMATOGRAPHY_SUMMARY formate in 90% acetonitrile, 10% water and 0.1% formic acid) with a gradient CH:CHROMATOGRAPHY_SUMMARY length of 30 min. CH:CHROMATOGRAPHY_TYPE HILIC CH:INSTRUMENT_NAME Thermo Vanquish CH:COLUMN_NAME Waters ACQUITY UPLC BEH HILIC (100 x 2.1mm,1.7um) CH:SOLVENT_A 90% water, 10% acetonitrile, 5mM Ammonium Formate, 0.1%FA CH:SOLVENT_B 10% water, 90% acetonitrile, 5mM Ammonium Formate, 0.1%FA CH:FLOW_GRADIENT 30 min CH:FLOW_RATE 0.20mL/min CH:COLUMN_TEMPERATURE 30 #ANALYSIS AN:ANALYSIS_TYPE MS #MS MS:INSTRUMENT_NAME Thermo Q Exactive HF hybrid Orbitrap MS:INSTRUMENT_TYPE Orbitrap MS:MS_TYPE ESI MS:ION_MODE POSITIVE MS:MS_COMMENTS Full MS analyses were acquired over the mass-to-charge ratio (m/z) range of MS:MS_COMMENTS 70-1,050 in positive ion mode. Full mass scan was acquired at 120,000 resolution MS:MS_COMMENTS with a scan rate of 3.5 Hz, automatic gain control (AGC) target of 1x106, and MS:MS_COMMENTS maximum ion injection time of 100 ms, and MS/MS spectra were collected at 15,000 MS:MS_COMMENTS resolution, AGC target of 2x105 ions, with a maximum ion injection time of 100 MS:MS_COMMENTS ms MS:MS_RESULTS_FILE ST002442_AN003979_Results.txt UNITS:time_m/z Has m/z:Yes Has RT:Yes RT units:Minutes #END