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Evaluation of disease progression in INCL by MR spectroscopy.

Baker EH, Levin SW, Zhang Z, Mukherjee AB - Ann Clin Transl Neurol (2015)

Bottom Line: In the cerebrum (affected early in the disease course), choline and myo-inositol were initially elevated and fell during the follow-up period, whereas in the cerebellum and brainstem (affected later), choline and myo-inositol were initially normal and rose subsequently.Low, persistently declining NAA was expected based on the progressive, irreversible nature of the disease.Progression of metabolite levels in INCL has not been previously quantified; therefore the results of this study serve as a reference for quantitative evaluation of future therapeutic interventions.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health Bethesda, Maryland, USA, 20892.

ABSTRACT

Objective: Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury. As part of a pilot study to evaluate treatment benefits of cysteamine bitartrate and N-acetylcysteine, we quantitatively measured brain metabolite levels using magnetic resonance spectroscopy (MRS).

Methods: A subset of two patients from a larger treatment and follow-up study underwent serial quantitative single-voxel MRS examinations of five anatomical sites. Three echo times were acquired in order to estimate metabolite T2. Measured metabolite levels included correction for partial volume of cerebrospinal fluid. Comparison of INCL patients was made to a reference group composed of asymptomatic and minimally symptomatic Niemann-Pick disease type C patients.

Results: In INCL patients, N-acetylaspartate (NAA) was abnormally low at all locations upon initial measurement, and further declined throughout the follow-up period. In the cerebrum (affected early in the disease course), choline and myo-inositol were initially elevated and fell during the follow-up period, whereas in the cerebellum and brainstem (affected later), choline and myo-inositol were initially normal and rose subsequently.

Interpretation: Choline and myo-inositol levels in our patients are consistent with patterns of neuroinflammation observed in two INCL mouse models. Low, persistently declining NAA was expected based on the progressive, irreversible nature of the disease. Progression of metabolite levels in INCL has not been previously quantified; therefore the results of this study serve as a reference for quantitative evaluation of future therapeutic interventions.

No MeSH data available.


Related in: MedlinePlus

T2 measurements, comparison of infantile neuronal ceroid lipofuscinosis (INCL) patients to the reference group. Squares and diamonds represent the individual INCL patients, while circles represent the reference group. In general, the T2 of the metabolites decreases with age for both the reference group and the INCL patients, but the decline is faster for the INCL patients. In such a situation, failing to correct for the relative difference in T2 would exaggerate the measured metabolite deficits in the INCL patients (shorter T2 simulates a lower metabolite signal when not included in the calculation). On all plots, the horizontal axis is age (in years) and the vertical axis is the T2 relaxation time of the main metabolite peak (in msec).
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fig01: T2 measurements, comparison of infantile neuronal ceroid lipofuscinosis (INCL) patients to the reference group. Squares and diamonds represent the individual INCL patients, while circles represent the reference group. In general, the T2 of the metabolites decreases with age for both the reference group and the INCL patients, but the decline is faster for the INCL patients. In such a situation, failing to correct for the relative difference in T2 would exaggerate the measured metabolite deficits in the INCL patients (shorter T2 simulates a lower metabolite signal when not included in the calculation). On all plots, the horizontal axis is age (in years) and the vertical axis is the T2 relaxation time of the main metabolite peak (in msec).

Mentions: Measurements of metabolite T2 for the INCL patients and the reference group are plotted in Figure1; the regression curves fitted to the measurements were subsequently used to correct the metabolite measurements for T2 decay. Selected points on the regression curves are presented in Table1. In most cases, the T2 curve in the INCL patients is lower than the T2 curve in the reference group, indicating a shorter T2 for the same age; in the rest of the cases, the T2 curves overlap and are effectively the same. The pathophysiology of INCL does not seem to result in lengthening of metabolite T2 at any of the locations that we studied. At most locations for most metabolites, for both the reference group and the INCL patients, T2 becomes shorter with age. In the reference group, the change is generally small over this age range, with the exception of choline in the white matter (LCSO and LCWM) and all 3 metabolites in the left thalamus. However, for the INCL patients, some of the metabolites at some of the locations had rather dramatic changes in metabolite T2 with age. For example, NAA at all locations except the pons, creatine in the LCWM, and choline in the white matter (LCSO and LCWM) all demonstrated large changes in metabolite T2 with age.


Evaluation of disease progression in INCL by MR spectroscopy.

Baker EH, Levin SW, Zhang Z, Mukherjee AB - Ann Clin Transl Neurol (2015)

T2 measurements, comparison of infantile neuronal ceroid lipofuscinosis (INCL) patients to the reference group. Squares and diamonds represent the individual INCL patients, while circles represent the reference group. In general, the T2 of the metabolites decreases with age for both the reference group and the INCL patients, but the decline is faster for the INCL patients. In such a situation, failing to correct for the relative difference in T2 would exaggerate the measured metabolite deficits in the INCL patients (shorter T2 simulates a lower metabolite signal when not included in the calculation). On all plots, the horizontal axis is age (in years) and the vertical axis is the T2 relaxation time of the main metabolite peak (in msec).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554441&req=5

fig01: T2 measurements, comparison of infantile neuronal ceroid lipofuscinosis (INCL) patients to the reference group. Squares and diamonds represent the individual INCL patients, while circles represent the reference group. In general, the T2 of the metabolites decreases with age for both the reference group and the INCL patients, but the decline is faster for the INCL patients. In such a situation, failing to correct for the relative difference in T2 would exaggerate the measured metabolite deficits in the INCL patients (shorter T2 simulates a lower metabolite signal when not included in the calculation). On all plots, the horizontal axis is age (in years) and the vertical axis is the T2 relaxation time of the main metabolite peak (in msec).
Mentions: Measurements of metabolite T2 for the INCL patients and the reference group are plotted in Figure1; the regression curves fitted to the measurements were subsequently used to correct the metabolite measurements for T2 decay. Selected points on the regression curves are presented in Table1. In most cases, the T2 curve in the INCL patients is lower than the T2 curve in the reference group, indicating a shorter T2 for the same age; in the rest of the cases, the T2 curves overlap and are effectively the same. The pathophysiology of INCL does not seem to result in lengthening of metabolite T2 at any of the locations that we studied. At most locations for most metabolites, for both the reference group and the INCL patients, T2 becomes shorter with age. In the reference group, the change is generally small over this age range, with the exception of choline in the white matter (LCSO and LCWM) and all 3 metabolites in the left thalamus. However, for the INCL patients, some of the metabolites at some of the locations had rather dramatic changes in metabolite T2 with age. For example, NAA at all locations except the pons, creatine in the LCWM, and choline in the white matter (LCSO and LCWM) all demonstrated large changes in metabolite T2 with age.

Bottom Line: In the cerebrum (affected early in the disease course), choline and myo-inositol were initially elevated and fell during the follow-up period, whereas in the cerebellum and brainstem (affected later), choline and myo-inositol were initially normal and rose subsequently.Low, persistently declining NAA was expected based on the progressive, irreversible nature of the disease.Progression of metabolite levels in INCL has not been previously quantified; therefore the results of this study serve as a reference for quantitative evaluation of future therapeutic interventions.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health Bethesda, Maryland, USA, 20892.

ABSTRACT

Objective: Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury. As part of a pilot study to evaluate treatment benefits of cysteamine bitartrate and N-acetylcysteine, we quantitatively measured brain metabolite levels using magnetic resonance spectroscopy (MRS).

Methods: A subset of two patients from a larger treatment and follow-up study underwent serial quantitative single-voxel MRS examinations of five anatomical sites. Three echo times were acquired in order to estimate metabolite T2. Measured metabolite levels included correction for partial volume of cerebrospinal fluid. Comparison of INCL patients was made to a reference group composed of asymptomatic and minimally symptomatic Niemann-Pick disease type C patients.

Results: In INCL patients, N-acetylaspartate (NAA) was abnormally low at all locations upon initial measurement, and further declined throughout the follow-up period. In the cerebrum (affected early in the disease course), choline and myo-inositol were initially elevated and fell during the follow-up period, whereas in the cerebellum and brainstem (affected later), choline and myo-inositol were initially normal and rose subsequently.

Interpretation: Choline and myo-inositol levels in our patients are consistent with patterns of neuroinflammation observed in two INCL mouse models. Low, persistently declining NAA was expected based on the progressive, irreversible nature of the disease. Progression of metabolite levels in INCL has not been previously quantified; therefore the results of this study serve as a reference for quantitative evaluation of future therapeutic interventions.

No MeSH data available.


Related in: MedlinePlus