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Déficits cognitivos são frequentes em pacientes com esclerose múltipla (EM), especialmente a memória de longo prazo. Por outro lado, estudos de imagem por ressonância magnética têm correlacionado atrofia do hipocampo aos déficits mnésicos destes pacientes. Considerando-se a atrofia um marcador de dano neuronal tardio, justifica-se a investigação da fisiopatologia do dano hipocampal nas fases inicias da doença. Objetivo: Descrever os achados volumétricos e neuroquímicos da formação hipocampal de pacientes com EM recorrente-remitente (EMRR) em suas fases iniciais, comparando-os ao de um grupo de indivíduos saudáveis, e avaliar suas relações com a memória de longo prazo. Material e Métodos: Vinte e nove pacientes (19 mulheres, idade média 31 anos ± 8,7) com EMRR e um grupo controle composto por 26 indivíduos saudáveis (19 mulheres, idade média 30,7 anos ± 8,4) realizaram a 1H-ERM em magneto 3,0T. Foi utilizada técnica single-voxel e sequência PRESS com TR = 1500 ms, TE = 135 ms e dimensões fixas do voxel (6 cm3) localizado ao longo do hipocampo esquerdo para avaliação do N-acetil-aspartato (NAA), Colina (Cho) e Creatina (Cr), sendo a análise feita com o software LC Model. A avaliação volumétrica do encéfalo e da formação hipocampal foi realizada por meio do software FreeSurfer. Os indivíduos foram avaliados cognitivamente tendo sido criado um escore de memória verbal que avalia a evocação tardia (EMV-T), empregando-se a etapa de evocação tardia do Hopkins Verbal Learning Test-Revised e o Teste da Memória Lógica-II. Resultados: Observou-se atrofia em ambos os hipocampos dos pacientes com EM. Além disso, pacientes apresentaram menores níveis de NAA quando comparados aos do grupo de controles (F(1,51) = 4,089; p = 0,048), tendo sido observada correlação positiva entre NAA e o volume da formação hipocampal no grupo de pacientes (r = 0,372; p = 0,047). Por fim, pacientes apresentaram correlação negativa significante entre EMV-T e NAA (r = -0,408; p = 0,031), Cho (r = -0,509; p = 0,006) e Cr (r = -0,402; p = 0,034), enquanto que, nos controles, apenas foi observada leve tendência de correlação na direção oposta. Conclusões: Nossos resultados indicam, nas fases inicias da EM, atrofia e redução dos níveis de NAA na formação hipocampal, secundário à disfunção e/ou perda neuronal. O fato dos pacientes apresentarem relação entre metabólitos hipocampais e memória oposta ao que é esperado, para indivíduos saudáveis, está de acordo com a hipótese da presença de mecanismos compensatórios na função cognitiva de pacientes com EM / Cognitive deficits are common in patients with multiple sclerosis (MS), especially long-term memory. Moreover, magnetic resonance imaging studies have correlated hippocampal atrophy with mnemonic deficits in these patients. Considering atrophy a late marker of neuronal damage, investigation of the pathophysiology of hippocampal damage in the early stages of the disease is justified. Objective: Describe the volumetric and neurochemical findings of the hippocampal formation of early relapsing-remitting MS patients (RRMS), comparing it to a group of healthy subjects, and assess its relationships with long-term memory. Material and Methods: Twenty-nine patients (19 women, mean age 31 years ± 8,7) with RRMS and a control group of 26 healthy individuals (19 women, mean age 30,7 anos ± 8,4) underwent 1H-MRS in 3,0T scanner. Single-voxel PRESS sequence with repetition time of 1500 msec, echo time of 135 msec and fixed dimensions of the voxel (6 cm3) was located along the left hippocampus. Data were processed with LC Model software and the concentration of N-acetyl-aspartate (NAA), Choline (Cho) and Creatine (Cr) was calculated. Brain and hippocampal formation volumes were quantified using FreeSurfer software. Subjects were assessed cognitively and a verbal memory score assessing delayed recall (EMV-T) was developed, using Hopkins Verbal Learning Test-Revised delayed recall and Logical Memory-II test. Results: Atrophy was observed in both hippocampi of MS patients. In addition, MS patients had lower NAA levels compared to the control group (F (1,51) = 4,089, p = 0,048), and positive correlation between NAA and hippocampal formation volume was observed in patient group (r = 0.372, p = 0.047). Finally, patients showed a significant negative correlation between EMV-T and NAA (r = -0.408, p = 0.031), Cho (r = -0.509, p = 0.006) and Cr (r = -0.402, p = 0.034), while only a weak tendency to an association in the opposite direction was observed in the control group. Conclusion: Our results indicate, in early MS, atrophy and reduced levels of NAA in the hippocampal formation, secondary to neuronal loss and/or dysfunction. The fact that the observed relationship between hippocampal metabolites and memory was in the opposite direction as what it is expected for healthy subjects supports the hypothesis that compensatory mechanisms are present in cognitive function of MS patients

Déficits cognitivos são frequentes em pacientes com esclerose múltipla (EM), especialmente a memória de longo prazo. Por outro lado, estudos de imagem por ressonância magnética têm correlacionado atrofia do hipocampo aos déficits mnésicos destes pacientes. Considerando-se a atrofia um marcador de dano neuronal tardio, justifica-se a investigação da fisiopatologia do dano hipocampal nas fases inicias da doença. Objetivo: Descrever os achados volumétricos e neuroquímicos da formação hipocampal de pacientes com EM recorrente-remitente (EMRR) em suas fases iniciais, comparando-os ao de um grupo de indivíduos saudáveis, e avaliar suas relações com a memória de longo prazo. Material e Métodos: Vinte e nove pacientes (19 mulheres, idade média 31 anos ± 8,7) com EMRR e um grupo controle composto por 26 indivíduos saudáveis (19 mulheres, idade média 30,7 anos ± 8,4) realizaram a 1H-ERM em magneto 3,0T. Foi utilizada técnica single-voxel e sequência PRESS com TR = 1500 ms, TE = 135 ms e dimensões fixas do voxel (6 cm3) localizado ao longo do hipocampo esquerdo para avaliação do N-acetil-aspartato (NAA), Colina (Cho) e Creatina (Cr), sendo a análise feita com o software LC Model. A avaliação volumétrica do encéfalo e da formação hipocampal foi realizada por meio do software FreeSurfer. Os indivíduos foram avaliados cognitivamente tendo sido criado um escore de memória verbal que avalia a evocação tardia (EMV-T), empregando-se a etapa de evocação tardia do Hopkins Verbal Learning Test-Revised e o Teste da Memória Lógica-II. Resultados: Observou-se atrofia em ambos os hipocampos dos pacientes com EM. Além disso, pacientes apresentaram menores níveis de NAA quando comparados aos do grupo de controles (F(1,51) = 4,089; p = 0,048), tendo sido observada correlação positiva entre NAA e o volume da formação hipocampal no grupo de pacientes (r = 0,372; p = 0,047). Por fim, pacientes apresentaram correlação negativa significante entre EMV-T e NAA (r = -0,408; p = 0,031), Cho (r = -0,509; p = 0,006) e Cr (r = -0,402; p = 0,034), enquanto que, nos controles, apenas foi observada leve tendência de correlação na direção oposta. Conclusões: Nossos resultados indicam, nas fases inicias da EM, atrofia e redução dos níveis de NAA na formação hipocampal, secundário à disfunção e/ou perda neuronal. O fato dos pacientes apresentarem relação entre metabólitos hipocampais e memória oposta ao que é esperado, para indivíduos saudáveis, está de acordo com a hipótese da presença de mecanismos compensatórios na função cognitiva de pacientes com EM / Cognitive deficits are common in patients with multiple sclerosis (MS), especially long-term memory. Moreover, magnetic resonance imaging studies have correlated hippocampal atrophy with mnemonic deficits in these patients. Considering atrophy a late marker of neuronal damage, investigation of the pathophysiology of hippocampal damage in the early stages of the disease is justified. Objective: Describe the volumetric and neurochemical findings of the hippocampal formation of early relapsing-remitting MS patients (RRMS), comparing it to a group of healthy subjects, and assess its relationships with long-term memory. Material and Methods: Twenty-nine patients (19 women, mean age 31 years ± 8,7) with RRMS and a control group of 26 healthy individuals (19 women, mean age 30,7 anos ± 8,4) underwent 1H-MRS in 3,0T scanner. Single-voxel PRESS sequence with repetition time of 1500 msec, echo time of 135 msec and fixed dimensions of the voxel (6 cm3) was located along the left hippocampus. Data were processed with LC Model software and the concentration of N-acetyl-aspartate (NAA), Choline (Cho) and Creatine (Cr) was calculated. Brain and hippocampal formation volumes were quantified using FreeSurfer software. Subjects were assessed cognitively and a verbal memory score assessing delayed recall (EMV-T) was developed, using Hopkins Verbal Learning Test-Revised delayed recall and Logical Memory-II test. Results: Atrophy was observed in both hippocampi of MS patients. In addition, MS patients had lower NAA levels compared to the control group (F (1,51) = 4,089, p = 0,048), and positive correlation between NAA and hippocampal formation volume was observed in patient group (r = 0.372, p = 0.047). Finally, patients showed a significant negative correlation between EMV-T and NAA (r = -0.408, p = 0.031), Cho (r = -0.509, p = 0.006) and Cr (r = -0.402, p = 0.034), while only a weak tendency to an association in the opposite direction was observed in the control group. Conclusion: Our results indicate, in early MS, atrophy and reduced levels of NAA in the hippocampal formation, secondary to neuronal loss and/or dysfunction. The fact that the observed relationship between hippocampal metabolites and memory was in the opposite direction as what it is expected for healthy subjects supports the hypothesis that compensatory mechanisms are present in cognitive function of MS patients

Ziele: Mittels absolutquantifizierender Protonen-Magnet-Resonanz-Spektroskopie (1H-MRS) wollten wir das Ergebnis einer Vorstudie bestätigen, die im Frontallappen einen reduzierten Quotienten von myo-Inositol/Gesamtcreatin (mI/tCr) bei Depressiven fand. Darüber hinaus testeten wir den antidepressiven Effekt von Inositol als Add-on-Therapie. Methodik: Wir untersuchten Einzelvoxel (2 x 2 x 2 cm3) in der weißen Substanz der rechten und linken Präfrontalregion mit Hilfe eines 3-Tesla Bruker Medspec Systems (STEAM Sequenz, TR/TE/TM = 6000/20/30 ms). Die einzelnen Metabolite wurden anhand des cerebralen Wassers als internem Standard quantifiziert (nach dem LCModell). Es wurden 24 unmedizierte Patienten mit unipolaren depressiven Episoden mit 24 alters- und geschlechtsgematchten gesunden Kontrollen verglichen. In doppelblindem, Plazebo-kontrollierten Parallelgruppen-Design erhielten die Patienten täglich 18 Gramm Inositol oder Plazebo zusätzlich zu Citalopram über vier Wochen. Ergebnisse: An der Baseline unterschieden sich die mI-, Cholin- und N-Acetyl-Aspartat-Konzentrationen der Patienten nicht von jenen der Kontrollen. Es fanden sich keine sich keine signifikanten Unterschiede zwischen Inositol- und Plazebo-Gruppe. Überraschenderweise zeigten die depressiven Patienten an der Baseline gegenüber den Kontrollen signifikant höhere tCr-Konzentrationen (mmol/kg) links (5,57 ± 0,96 vs. 4,87 ± 0,63; + 15 %, p < 0,01) und rechts präfrontal (5,29 ± 0,92 vs. 4,46 ± 0,41; + 17 %, p < 0,01). Nach der Behandlung ergab sich eine Reduktion der tCr-Konzentration links- (Tag 28: 5,05 ± 1,16; – 12 %, p = 0,08) und rechtsfrontal (Tag 28: 4,61 ± 1,07; – 9 %, p = 0,09). Die tCr-Konzentrationen der Patienten am Tag 28 unterschieden sich nicht mehr von jenen der Kontrollen. Zusammenfassung: Wir zeigten eine reversible Steigerung der tCr-Konzentration der Patienten im Vergleich zu Kontrollen, die auf Veränderungen des Creatin-Transports oder der ATP-Synthese bei unmedizierter unipolarer Depression hinweisen könnte. / Objectives: By means of proton magnetic resonance spectroscopy (1H-MRS) with absolute quantification we wanted to confirm our previous finding of decreased ratios of the metabolites myo-Inositol/total creatine (mI/tCr) in the right frontal brain of depressives. Moreover, we tested the antidepressive effect of oral Inositol ingestion as add-on-therapy. We measured concentrations (mmol/kg ww) of mI, tCr (= Creatine + Phosphocreatine), Choline (Cho) and N-Acetyl-Aspartate (NAA) in the frontal brain. Methods: Single voxels (2x2x2 cm3) in the white matter of the left and right prefrontal region were examined in a three Tesla Bruker Medspec System (STEAM sequence, TR/TE/TM = 6000/20/30 ms). Metabolites were quantified using the LCModel. At baseline, 24 drug-free patients with unipolar depressive episodes were compared to 24 age and sex matched healthy controls. In a double blind, placebo controlled parallel-group design patients received daily 18 grams Inositol or placebo as an add on therapy to Citalopram over four weeks. Results: At baseline, mI, Cho and NAA concentrations showed no significant differences between patients and controls. The treatment with Inositol did not result in any significant differences to the treatment with placebo. Surprisingly the patients showed significant higher tCr concentrations in the left (5.57 ± 0.96 vs. 4.87 ± 0.63; + 15 %, p < 0.01) as well as in the right prefrontal region (5.29 ± 0.92 vs. 4.46 ± 0.41; + 17 %, p < 0.01) compared to controls. The treatment caused a trend towards a decrease of tCr in the left (day 28: 5.05 ± 1.16; – 12 %, p = 0.08) and in the right frontal hemisphere (day 28: 4.61 ± 1.07; – 9 %, p = 0.09) compared to baseline. The differences between the patients’ tCr at day 28 and the tCr of controls were no more significant. Conclusion: We have found a state dependent increase of tCr concentration indicating bifrontal deviations in Creatine transport or ATP synthesis in drug free unipolar depressives.