title: High-resolution magic angle spinning and 1H magnetic resonance spectroscopy reveal significantly altered neuronal metabolite profiles in CLN1 but not in CLN3.
abstract: The neuronal ceroid lipofuscinoses (NCLs) are among the most severe inherited progressive neurodegenerative disorders of children. The purpose of this study was to compare the in vivo 1.5-T 1H magnetic resonance (MR) and ex vivo 14.3-T high-resolution (HR) magic angle spinning (MAS) 1H MR brain spectra of patients with infantile (CLN1) and juvenile (CLN3) types of NCL, to obtain detailed information about the alterations in the neuronal metabolite profiles in these diseases and to test the suitability of the ex vivo HR MAS (1)H MRS technique in analysis of autopsy brain tissue. Ex vivo spectra from CLN1 autopsy brain tissue (n = 9) significantly differed from those of the control (n = 9) and CLN3 (n = 5) groups, although no differences were found between the CLN3 and the control groups. Principal component analysis of ex vivo data showed that decreased levels of N-acetylaspartate (NAA), gamma-aminobutyric acid (GABA), glutamine, and glutamate as well as increased levels of inositols characterized the CLN1 spectra. Also, the intensity ratio of lipid methylene/methyl protons was decreased in spectra of CLN1 brain tissue compared with CLN3 and control brain tissue. In concordance with the ex vivo data, the in vivo spectra of late-stage patients with CLN1 (n = 3) revealed a dramatic decrease of NAA and a proportional increase of myo-inositol and lipids compared with control subjects. Again, the spectra of patients with CLN3 (n = 13) did not differ from those of controls (n = 15). In conclusion, the ex vivo and in vivo spectroscopic findings were in good agreement within all analyzed groups and revealed significant alterations in metabolite profiles in CLN1 brain tissue but not in CLN3 compared with controls. Furthermore, HR MAS 1H MR spectra facilitated refined detection of neuronal metabolites, including GABA, and composition of lipids in the autopsy brain tissue of NCL patients.
authors.affiliation: SINTEF Unimed, Trondheim, Norway.
authors.forename: Beathe
authors.initials: B
authors.lastname: Sitter
authors.forename: Taina
authors.initials: T
authors.lastname: Autti
authors.forename: Jaana
authors.initials: J
authors.lastname: Tyynelä
authors.forename: Ursula
authors.initials: U
authors.lastname: Sonnewald
authors.forename: Tone F
authors.initials: TF
authors.lastname: Bathen
authors.forename: Johanna
authors.initials: J
authors.lastname: Puranen
authors.forename: Pirkko
authors.initials: P
authors.lastname: Santavuori
authors.forename: Matti J
authors.initials: MJ
authors.lastname: Haltia
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Tuomo
authors.initials: T
authors.lastname: Polvikoski
authors.forename: Ingrid S
authors.initials: IS
authors.lastname: Gribbestad
authors.forename: Anna-Maija
authors.initials: AM
authors.lastname: Häkkinen
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000032:analysis; D001921:Brain / Q000033:anatomy & histology / Q000473:pathology; D001923:Brain Chemistry / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D002794:Choline / Q000032:analysis; D003401:Creatine / Q000032:analysis; D005260:Female; D018698:Glutamic Acid / Q000032:analysis; D005973:Glutamine / Q000032:analysis; D006801:Humans; D007294:Inositol / Q000032:analysis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000145:classification / Q000175:diagnosis*; D009474:Neurons / Q000737:chemistry* / Q000378:metabolism; D013869:Thiolester Hydrolases; D005680:gamma-Aminobutyric Acid / Q000032:analysis
chemical_list: C105199:CLN3 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D005973:Glutamine; D001224:Aspartic Acid; D018698:Glutamic Acid; D007294:Inositol; D005680:gamma-Aminobutyric Acid; C000179:N-acetylaspartate; D013869:Thiolester Hydrolases; C416054:PPT1 protein, human; D003401:Creatine; D002794:Choline