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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

Comparison of INCL patients to the reference group. Squares and diamonds represent the individual INCL patients, while circles represent the reference group. These results have not been corrected for the T2 of the metabolites. (Due to the complex nature of the mI and Glx peaks, the T2 could not be estimated from the data we collected. If mI and Glx follow the pattern of Cho, Cr, and NAA, then not correcting for a shorter T2 would exaggerate deficits and minimize elevations.) The pattern of myo-inositol appears to follow a temporal sequence of being initially normal, followed by elevation and then decline, with the sequence playing out earliest in the parietal gray matter, followed by the thalamus and centrum semiovale, then the cerebellar white matter, and last in the pons. The deficits of Glx parallel the deficits of NAA that are shown in Figure1. On all plots, the horizontal axis is age (in years) and the vertical axis is tissue metabolite concentration (in mmol/L). INCL, infantile neuronal ceroid lipofuscinosis; mI, myo-inositol; Glx, glutamine + glutamate + GABA; Cho, choline; Cr, creatine; NAA, N-acetylaspartate.
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fig03: Comparison of INCL patients to the reference group. Squares and diamonds represent the individual INCL patients, while circles represent the reference group. These results have not been corrected for the T2 of the metabolites. (Due to the complex nature of the mI and Glx peaks, the T2 could not be estimated from the data we collected. If mI and Glx follow the pattern of Cho, Cr, and NAA, then not correcting for a shorter T2 would exaggerate deficits and minimize elevations.) The pattern of myo-inositol appears to follow a temporal sequence of being initially normal, followed by elevation and then decline, with the sequence playing out earliest in the parietal gray matter, followed by the thalamus and centrum semiovale, then the cerebellar white matter, and last in the pons. The deficits of Glx parallel the deficits of NAA that are shown in Figure1. On all plots, the horizontal axis is age (in years) and the vertical axis is tissue metabolite concentration (in mmol/L). INCL, infantile neuronal ceroid lipofuscinosis; mI, myo-inositol; Glx, glutamine + glutamate + GABA; Cho, choline; Cr, creatine; NAA, N-acetylaspartate.

Mentions: The pattern of Glx in the INCL patients (Figure3, right column) compared to the reference group generally parallels the findings in NAA, but the trends are weaker and the differences between the INCL and reference groups are less obvious, at least in part due to the greater uncertainty in the Glx measurements. Glx deficit was the greatest in the PGM, almost as large in the left thalamus, and least in the LCSO and pons. Glx seemed relatively normal in the LCWM.


Evaluation of disease progression in INCL by MR spectroscopy.

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

Comparison of INCL patients to the reference group. Squares and diamonds represent the individual INCL patients, while circles represent the reference group. These results have not been corrected for the T2 of the metabolites. (Due to the complex nature of the mI and Glx peaks, the T2 could not be estimated from the data we collected. If mI and Glx follow the pattern of Cho, Cr, and NAA, then not correcting for a shorter T2 would exaggerate deficits and minimize elevations.) The pattern of myo-inositol appears to follow a temporal sequence of being initially normal, followed by elevation and then decline, with the sequence playing out earliest in the parietal gray matter, followed by the thalamus and centrum semiovale, then the cerebellar white matter, and last in the pons. The deficits of Glx parallel the deficits of NAA that are shown in Figure1. On all plots, the horizontal axis is age (in years) and the vertical axis is tissue metabolite concentration (in mmol/L). INCL, infantile neuronal ceroid lipofuscinosis; mI, myo-inositol; Glx, glutamine + glutamate + GABA; Cho, choline; Cr, creatine; NAA, N-acetylaspartate.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: Comparison of INCL patients to the reference group. Squares and diamonds represent the individual INCL patients, while circles represent the reference group. These results have not been corrected for the T2 of the metabolites. (Due to the complex nature of the mI and Glx peaks, the T2 could not be estimated from the data we collected. If mI and Glx follow the pattern of Cho, Cr, and NAA, then not correcting for a shorter T2 would exaggerate deficits and minimize elevations.) The pattern of myo-inositol appears to follow a temporal sequence of being initially normal, followed by elevation and then decline, with the sequence playing out earliest in the parietal gray matter, followed by the thalamus and centrum semiovale, then the cerebellar white matter, and last in the pons. The deficits of Glx parallel the deficits of NAA that are shown in Figure1. On all plots, the horizontal axis is age (in years) and the vertical axis is tissue metabolite concentration (in mmol/L). INCL, infantile neuronal ceroid lipofuscinosis; mI, myo-inositol; Glx, glutamine + glutamate + GABA; Cho, choline; Cr, creatine; NAA, N-acetylaspartate.
Mentions: The pattern of Glx in the INCL patients (Figure3, right column) compared to the reference group generally parallels the findings in NAA, but the trends are weaker and the differences between the INCL and reference groups are less obvious, at least in part due to the greater uncertainty in the Glx measurements. Glx deficit was the greatest in the PGM, almost as large in the left thalamus, and least in the LCSO and pons. Glx seemed relatively normal in the LCWM.

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