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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

Relationships between the metabolites. Upper left: The relationship between creatine and NAA is linear. In white matter, the fit for INCL does not project into the reference cluster, suggesting that creatine in the WM persists for a while after the NAA starts dropping. Middle left: The relationship between Glx and NAA is linear. In gray matter, the fit for INCL does not project into the reference cluster, suggesting that loss of Glx precedes loss of NAA. Lower left: the relationship between creatine and Glx is also linear, and the timing pattern is consistent with the other two plots. Upper right: In the reference group, choline seems independent of NAA in the WM and weakly correlated in the GM, with a generally higher choline in the WM than in the GM. In INCL, the choline initially rises and later falls as the disease progresses, with GM leading WM (quadratic fits are shown, although other models may be better). Middle right: There is a weak linear correlation between myo-inositol and NAA in the reference group, with myo-inositol in the WM and GM essentially equal. In INCL, GM and WM deviate from normal at about the same time, but GM progresses faster into the falling phase. Lower right: In the reference group, choline and myo-inositol appeared to be independent of one another; choline was higher in WM than GM, while myo-inositol was about the same. In INCL, there was a strong linear relationship between choline and myo-inositol, which were both elevated in white matter. NAA, N-acetylaspartate; INCL, infantile neuronal ceroid lipofuscinosis; WM, white matter; Glx, glutamine + glutamate + GABA; GM, gray matter.
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fig04: Relationships between the metabolites. Upper left: The relationship between creatine and NAA is linear. In white matter, the fit for INCL does not project into the reference cluster, suggesting that creatine in the WM persists for a while after the NAA starts dropping. Middle left: The relationship between Glx and NAA is linear. In gray matter, the fit for INCL does not project into the reference cluster, suggesting that loss of Glx precedes loss of NAA. Lower left: the relationship between creatine and Glx is also linear, and the timing pattern is consistent with the other two plots. Upper right: In the reference group, choline seems independent of NAA in the WM and weakly correlated in the GM, with a generally higher choline in the WM than in the GM. In INCL, the choline initially rises and later falls as the disease progresses, with GM leading WM (quadratic fits are shown, although other models may be better). Middle right: There is a weak linear correlation between myo-inositol and NAA in the reference group, with myo-inositol in the WM and GM essentially equal. In INCL, GM and WM deviate from normal at about the same time, but GM progresses faster into the falling phase. Lower right: In the reference group, choline and myo-inositol appeared to be independent of one another; choline was higher in WM than GM, while myo-inositol was about the same. In INCL, there was a strong linear relationship between choline and myo-inositol, which were both elevated in white matter. NAA, N-acetylaspartate; INCL, infantile neuronal ceroid lipofuscinosis; WM, white matter; Glx, glutamine + glutamate + GABA; GM, gray matter.

Mentions: Relationships between the metabolites are plotted in Figure4. NAA, Glx, and creatine are all linearly related to each other. The plots demonstrate that in GM, the drop in Glx precedes the drop in NAA, and that in WM, the drop in NAA precedes the drop in creatine. Myo-inositol and choline have a linear relationship to each other in the INCL patients, but appear to be unrelated in the reference group. Relative to NAA, both myo-inositol and choline initially rise as NAA drops, and later decline as NAA drops further. For choline, the initial rise occurs earlier in GM than in WM, and for myo-inositol, the late drop off occurs later in WM than in GM.


Evaluation of disease progression in INCL by MR spectroscopy.

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

Relationships between the metabolites. Upper left: The relationship between creatine and NAA is linear. In white matter, the fit for INCL does not project into the reference cluster, suggesting that creatine in the WM persists for a while after the NAA starts dropping. Middle left: The relationship between Glx and NAA is linear. In gray matter, the fit for INCL does not project into the reference cluster, suggesting that loss of Glx precedes loss of NAA. Lower left: the relationship between creatine and Glx is also linear, and the timing pattern is consistent with the other two plots. Upper right: In the reference group, choline seems independent of NAA in the WM and weakly correlated in the GM, with a generally higher choline in the WM than in the GM. In INCL, the choline initially rises and later falls as the disease progresses, with GM leading WM (quadratic fits are shown, although other models may be better). Middle right: There is a weak linear correlation between myo-inositol and NAA in the reference group, with myo-inositol in the WM and GM essentially equal. In INCL, GM and WM deviate from normal at about the same time, but GM progresses faster into the falling phase. Lower right: In the reference group, choline and myo-inositol appeared to be independent of one another; choline was higher in WM than GM, while myo-inositol was about the same. In INCL, there was a strong linear relationship between choline and myo-inositol, which were both elevated in white matter. NAA, N-acetylaspartate; INCL, infantile neuronal ceroid lipofuscinosis; WM, white matter; Glx, glutamine + glutamate + GABA; GM, gray matter.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: Relationships between the metabolites. Upper left: The relationship between creatine and NAA is linear. In white matter, the fit for INCL does not project into the reference cluster, suggesting that creatine in the WM persists for a while after the NAA starts dropping. Middle left: The relationship between Glx and NAA is linear. In gray matter, the fit for INCL does not project into the reference cluster, suggesting that loss of Glx precedes loss of NAA. Lower left: the relationship between creatine and Glx is also linear, and the timing pattern is consistent with the other two plots. Upper right: In the reference group, choline seems independent of NAA in the WM and weakly correlated in the GM, with a generally higher choline in the WM than in the GM. In INCL, the choline initially rises and later falls as the disease progresses, with GM leading WM (quadratic fits are shown, although other models may be better). Middle right: There is a weak linear correlation between myo-inositol and NAA in the reference group, with myo-inositol in the WM and GM essentially equal. In INCL, GM and WM deviate from normal at about the same time, but GM progresses faster into the falling phase. Lower right: In the reference group, choline and myo-inositol appeared to be independent of one another; choline was higher in WM than GM, while myo-inositol was about the same. In INCL, there was a strong linear relationship between choline and myo-inositol, which were both elevated in white matter. NAA, N-acetylaspartate; INCL, infantile neuronal ceroid lipofuscinosis; WM, white matter; Glx, glutamine + glutamate + GABA; GM, gray matter.
Mentions: Relationships between the metabolites are plotted in Figure4. NAA, Glx, and creatine are all linearly related to each other. The plots demonstrate that in GM, the drop in Glx precedes the drop in NAA, and that in WM, the drop in NAA precedes the drop in creatine. Myo-inositol and choline have a linear relationship to each other in the INCL patients, but appear to be unrelated in the reference group. Relative to NAA, both myo-inositol and choline initially rise as NAA drops, and later decline as NAA drops further. For choline, the initial rise occurs earlier in GM than in WM, and for myo-inositol, the late drop off occurs later in WM than in GM.

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