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suggesting that it may be worthwhile to examine the correction of low levels as a means of slowing disease progression.
Investigators led by Chadwick W. Christine, MD, of the department of neurology at the University of California, San Francisco, sought to understand what contributes to considerable variation in the progression of PD by building on previous research that revealed low serum vitamin B12 levels are common in patients with moderately advanced PD and are associated with neuropathy and cognitive impairment.
They measured serum methylmalonic acid, homocysteine, and holotranscobalamin in addition to B12 because of the limited sensitivity of serum B12 testing alone to detect B12 deficiency. At baseline, 13% of 680 patients had borderline-low B12 levels (less than 184 pmol/L [250 pg/mL]), and 5% had deficient B12 levels (less than 157 pmol/L or 212 pg/mL). Homocysteine was moderately elevated (greater than 15 mmol/L) in 7% of subjects, and 14% of patients with borderline-low B12 also had elevated homocysteine, the investigators reported in Movement Disorders.
Low B12 at baseline predicted greater worsening of mobility in terms of a higher ambulatory capacity score, calculated by adding individual items of the Unified Parkinson’s Disease Rating Scale (UPDRS): falling, freezing when walking, walking, gait, and postural stability. Participants in the low- B12 tertile (less than 234 pmol/L or 317 pg/ mL) developed greater morbidity as assessed by greater annualized worsening of the ambulatory capacity score. For example, those in the low-B12 tertile had annualized change of 1.53, compared with 0.77 in the upper tertile. The worsening score was mostly attributed to poorer gait and postural instability.
To give context to these figures, the researchers pointed to an analysis of the NET-PD LS1 cohort that found a mean ambulatory capacity score of 2.17 among patients who fell and a score of 1.4 for those who did not fall. “Thus, we consider the magnitude of difference to be clinically relevant, particularly given that components of gait dysfunction that develop in PD may not respond to dopaminergic treatments or [deep brain stimulation],” they wrote.
Elevated homocysteine also predicted greater cognitive decline. Baseline elevated homocysteine was associated with lower baseline Mini Mental State Examination (MMSE), as well as greater annualized decline in MMSE (–1.96 vs. 0.06; P = .001).
Of the 456 subjects who continued in the study for 9-24 months and had a second blood sample available, 226 had an increase of more than 20% in B12 levels, 210 stayed within 20% of the original B12 measurement, and 19 had a decrease greater than 20%.
Overall, there was a mean annualized increase in B12 of 52.6 pmol/L, a mean annualized decrease of homocysteine of 0.83 mmol/L, and a mean annualized increase of holotranscobalamin of 14.7 pmol/L.
“These findings are consistent with improved nutritional status during the course of the study, likely attributed to subjects starting the optional [multivitamin] after the baseline visit and/or subjects changing their diets,” the research team said.
While the improvement in B12 status did not lead to statistically significant improvements in UPDRS scores, the researchers said there was a trend toward improvement, which provides “support for a disease-modifying effect of B12,” they wrote.
The researchers speculated that their findings of a link between low B12 levels and worse outcomes could be attributed to an independent (comorbid) effect on the central and peripheral nervous systems, a direct effect on PD pathogenesis, or alternatively, that low B12 may be a marker of an unknown associated factor.
“Given that low B12 status is associated with neurological and other medical morbidities and is readily treated, great care would be needed to design an ethically acceptable randomized, prospective study to evaluate the effect of B12 supplementation on PD progression, given that serum measurements collected as part of a prospective study in unsupplemented patients would likely reveal some subjects with B12 deficiency,” they concluded.
The authors declared no relevant disclosures. The study was supported by a grant from the Michael J. Fox Foundation for Parkinson’s Research, as well as privately donated grants.
SOURCE: Christine C et al. Movement Dis. 2018 Mar 6. doi: 10.1002/mds.27301.
The course of PD can be quite variable, and it is difficult for clinicians to predict what will happen to an individual person with PD, but identifying prognostic factors ought to help practitioners answer their patients’ questions and potentially improve the understanding of mechanisms underlying the disease pathogenesis.
If vitamin B12 is related to the progression of PD as suggested in the study by Christine et al., its replacement may slow the decline of the disease. But there are several issues that need to be addressed in the context of their findings.
First, what constitutes a low vitamin B12 level is not a simple issue. If the evaluation is limited to measurement of vitamin B12 concentration, the diagnosis of genuine deficiency is unreliable. Most experts agree that combined measurement of vitamin B12 with determination of homocysteine levels is necessary and while Christine et al. measured both levels, their statistical analysis and subsequent conclusions are exclusively based on the levels of the vitamin.
Moreover, 34 patients in the study were classified as having “borderline-low” vitamin B12 levels, and 14 had both borderline-low B12 level and high homocysteine concentration. This brings into question whether the researchers identified PD patients who actually had low B12 levels.
The design of the DATATOP trial could also introduce some bias into the findings. At the time of publication, the study was criticized for disregarding the symptomatic effect of selegiline and for a lack of objective definition of criteria for the trial’s primary endpoint – introduction of levodopa.
This could have led to the termination of individuals at different stages of the disease, introducing a potential bias in the sample of patients who remained in the study for enough time to undergo subsequent determination of B12 levels.
The findings in the current study are also in contrast to previous research, and the underlying mechanism of vitamin B12 in PD is also unclear.
Nevertheless, the results of the study by Dr. Christine and his colleagues are intriguing and further investigations to address this hypothesis are warranted.
Francisco Cardoso, MD, PhD, is with the movement disorders unit within the neurology service at the Federal University of Minas Gerais, Belo Horizonte, Brazil. His comments are derived from an editorial accompanying the study by Dr. Christine and colleagues (Movement Dis. 2018 Mar 6. doi: 10.1002/mds.27366). He had no relevant disclosures.
The course of PD can be quite variable, and it is difficult for clinicians to predict what will happen to an individual person with PD, but identifying prognostic factors ought to help practitioners answer their patients’ questions and potentially improve the understanding of mechanisms underlying the disease pathogenesis.
If vitamin B12 is related to the progression of PD as suggested in the study by Christine et al., its replacement may slow the decline of the disease. But there are several issues that need to be addressed in the context of their findings.
First, what constitutes a low vitamin B12 level is not a simple issue. If the evaluation is limited to measurement of vitamin B12 concentration, the diagnosis of genuine deficiency is unreliable. Most experts agree that combined measurement of vitamin B12 with determination of homocysteine levels is necessary and while Christine et al. measured both levels, their statistical analysis and subsequent conclusions are exclusively based on the levels of the vitamin.
Moreover, 34 patients in the study were classified as having “borderline-low” vitamin B12 levels, and 14 had both borderline-low B12 level and high homocysteine concentration. This brings into question whether the researchers identified PD patients who actually had low B12 levels.
The design of the DATATOP trial could also introduce some bias into the findings. At the time of publication, the study was criticized for disregarding the symptomatic effect of selegiline and for a lack of objective definition of criteria for the trial’s primary endpoint – introduction of levodopa.
This could have led to the termination of individuals at different stages of the disease, introducing a potential bias in the sample of patients who remained in the study for enough time to undergo subsequent determination of B12 levels.
The findings in the current study are also in contrast to previous research, and the underlying mechanism of vitamin B12 in PD is also unclear.
Nevertheless, the results of the study by Dr. Christine and his colleagues are intriguing and further investigations to address this hypothesis are warranted.
Francisco Cardoso, MD, PhD, is with the movement disorders unit within the neurology service at the Federal University of Minas Gerais, Belo Horizonte, Brazil. His comments are derived from an editorial accompanying the study by Dr. Christine and colleagues (Movement Dis. 2018 Mar 6. doi: 10.1002/mds.27366). He had no relevant disclosures.
The course of PD can be quite variable, and it is difficult for clinicians to predict what will happen to an individual person with PD, but identifying prognostic factors ought to help practitioners answer their patients’ questions and potentially improve the understanding of mechanisms underlying the disease pathogenesis.
If vitamin B12 is related to the progression of PD as suggested in the study by Christine et al., its replacement may slow the decline of the disease. But there are several issues that need to be addressed in the context of their findings.
First, what constitutes a low vitamin B12 level is not a simple issue. If the evaluation is limited to measurement of vitamin B12 concentration, the diagnosis of genuine deficiency is unreliable. Most experts agree that combined measurement of vitamin B12 with determination of homocysteine levels is necessary and while Christine et al. measured both levels, their statistical analysis and subsequent conclusions are exclusively based on the levels of the vitamin.
Moreover, 34 patients in the study were classified as having “borderline-low” vitamin B12 levels, and 14 had both borderline-low B12 level and high homocysteine concentration. This brings into question whether the researchers identified PD patients who actually had low B12 levels.
The design of the DATATOP trial could also introduce some bias into the findings. At the time of publication, the study was criticized for disregarding the symptomatic effect of selegiline and for a lack of objective definition of criteria for the trial’s primary endpoint – introduction of levodopa.
This could have led to the termination of individuals at different stages of the disease, introducing a potential bias in the sample of patients who remained in the study for enough time to undergo subsequent determination of B12 levels.
The findings in the current study are also in contrast to previous research, and the underlying mechanism of vitamin B12 in PD is also unclear.
Nevertheless, the results of the study by Dr. Christine and his colleagues are intriguing and further investigations to address this hypothesis are warranted.
Francisco Cardoso, MD, PhD, is with the movement disorders unit within the neurology service at the Federal University of Minas Gerais, Belo Horizonte, Brazil. His comments are derived from an editorial accompanying the study by Dr. Christine and colleagues (Movement Dis. 2018 Mar 6. doi: 10.1002/mds.27366). He had no relevant disclosures.
suggesting that it may be worthwhile to examine the correction of low levels as a means of slowing disease progression.
Investigators led by Chadwick W. Christine, MD, of the department of neurology at the University of California, San Francisco, sought to understand what contributes to considerable variation in the progression of PD by building on previous research that revealed low serum vitamin B12 levels are common in patients with moderately advanced PD and are associated with neuropathy and cognitive impairment.
They measured serum methylmalonic acid, homocysteine, and holotranscobalamin in addition to B12 because of the limited sensitivity of serum B12 testing alone to detect B12 deficiency. At baseline, 13% of 680 patients had borderline-low B12 levels (less than 184 pmol/L [250 pg/mL]), and 5% had deficient B12 levels (less than 157 pmol/L or 212 pg/mL). Homocysteine was moderately elevated (greater than 15 mmol/L) in 7% of subjects, and 14% of patients with borderline-low B12 also had elevated homocysteine, the investigators reported in Movement Disorders.
Low B12 at baseline predicted greater worsening of mobility in terms of a higher ambulatory capacity score, calculated by adding individual items of the Unified Parkinson’s Disease Rating Scale (UPDRS): falling, freezing when walking, walking, gait, and postural stability. Participants in the low- B12 tertile (less than 234 pmol/L or 317 pg/ mL) developed greater morbidity as assessed by greater annualized worsening of the ambulatory capacity score. For example, those in the low-B12 tertile had annualized change of 1.53, compared with 0.77 in the upper tertile. The worsening score was mostly attributed to poorer gait and postural instability.
To give context to these figures, the researchers pointed to an analysis of the NET-PD LS1 cohort that found a mean ambulatory capacity score of 2.17 among patients who fell and a score of 1.4 for those who did not fall. “Thus, we consider the magnitude of difference to be clinically relevant, particularly given that components of gait dysfunction that develop in PD may not respond to dopaminergic treatments or [deep brain stimulation],” they wrote.
Elevated homocysteine also predicted greater cognitive decline. Baseline elevated homocysteine was associated with lower baseline Mini Mental State Examination (MMSE), as well as greater annualized decline in MMSE (–1.96 vs. 0.06; P = .001).
Of the 456 subjects who continued in the study for 9-24 months and had a second blood sample available, 226 had an increase of more than 20% in B12 levels, 210 stayed within 20% of the original B12 measurement, and 19 had a decrease greater than 20%.
Overall, there was a mean annualized increase in B12 of 52.6 pmol/L, a mean annualized decrease of homocysteine of 0.83 mmol/L, and a mean annualized increase of holotranscobalamin of 14.7 pmol/L.
“These findings are consistent with improved nutritional status during the course of the study, likely attributed to subjects starting the optional [multivitamin] after the baseline visit and/or subjects changing their diets,” the research team said.
While the improvement in B12 status did not lead to statistically significant improvements in UPDRS scores, the researchers said there was a trend toward improvement, which provides “support for a disease-modifying effect of B12,” they wrote.
The researchers speculated that their findings of a link between low B12 levels and worse outcomes could be attributed to an independent (comorbid) effect on the central and peripheral nervous systems, a direct effect on PD pathogenesis, or alternatively, that low B12 may be a marker of an unknown associated factor.
“Given that low B12 status is associated with neurological and other medical morbidities and is readily treated, great care would be needed to design an ethically acceptable randomized, prospective study to evaluate the effect of B12 supplementation on PD progression, given that serum measurements collected as part of a prospective study in unsupplemented patients would likely reveal some subjects with B12 deficiency,” they concluded.
The authors declared no relevant disclosures. The study was supported by a grant from the Michael J. Fox Foundation for Parkinson’s Research, as well as privately donated grants.
SOURCE: Christine C et al. Movement Dis. 2018 Mar 6. doi: 10.1002/mds.27301.
suggesting that it may be worthwhile to examine the correction of low levels as a means of slowing disease progression.
Investigators led by Chadwick W. Christine, MD, of the department of neurology at the University of California, San Francisco, sought to understand what contributes to considerable variation in the progression of PD by building on previous research that revealed low serum vitamin B12 levels are common in patients with moderately advanced PD and are associated with neuropathy and cognitive impairment.
They measured serum methylmalonic acid, homocysteine, and holotranscobalamin in addition to B12 because of the limited sensitivity of serum B12 testing alone to detect B12 deficiency. At baseline, 13% of 680 patients had borderline-low B12 levels (less than 184 pmol/L [250 pg/mL]), and 5% had deficient B12 levels (less than 157 pmol/L or 212 pg/mL). Homocysteine was moderately elevated (greater than 15 mmol/L) in 7% of subjects, and 14% of patients with borderline-low B12 also had elevated homocysteine, the investigators reported in Movement Disorders.
Low B12 at baseline predicted greater worsening of mobility in terms of a higher ambulatory capacity score, calculated by adding individual items of the Unified Parkinson’s Disease Rating Scale (UPDRS): falling, freezing when walking, walking, gait, and postural stability. Participants in the low- B12 tertile (less than 234 pmol/L or 317 pg/ mL) developed greater morbidity as assessed by greater annualized worsening of the ambulatory capacity score. For example, those in the low-B12 tertile had annualized change of 1.53, compared with 0.77 in the upper tertile. The worsening score was mostly attributed to poorer gait and postural instability.
To give context to these figures, the researchers pointed to an analysis of the NET-PD LS1 cohort that found a mean ambulatory capacity score of 2.17 among patients who fell and a score of 1.4 for those who did not fall. “Thus, we consider the magnitude of difference to be clinically relevant, particularly given that components of gait dysfunction that develop in PD may not respond to dopaminergic treatments or [deep brain stimulation],” they wrote.
Elevated homocysteine also predicted greater cognitive decline. Baseline elevated homocysteine was associated with lower baseline Mini Mental State Examination (MMSE), as well as greater annualized decline in MMSE (–1.96 vs. 0.06; P = .001).
Of the 456 subjects who continued in the study for 9-24 months and had a second blood sample available, 226 had an increase of more than 20% in B12 levels, 210 stayed within 20% of the original B12 measurement, and 19 had a decrease greater than 20%.
Overall, there was a mean annualized increase in B12 of 52.6 pmol/L, a mean annualized decrease of homocysteine of 0.83 mmol/L, and a mean annualized increase of holotranscobalamin of 14.7 pmol/L.
“These findings are consistent with improved nutritional status during the course of the study, likely attributed to subjects starting the optional [multivitamin] after the baseline visit and/or subjects changing their diets,” the research team said.
While the improvement in B12 status did not lead to statistically significant improvements in UPDRS scores, the researchers said there was a trend toward improvement, which provides “support for a disease-modifying effect of B12,” they wrote.
The researchers speculated that their findings of a link between low B12 levels and worse outcomes could be attributed to an independent (comorbid) effect on the central and peripheral nervous systems, a direct effect on PD pathogenesis, or alternatively, that low B12 may be a marker of an unknown associated factor.
“Given that low B12 status is associated with neurological and other medical morbidities and is readily treated, great care would be needed to design an ethically acceptable randomized, prospective study to evaluate the effect of B12 supplementation on PD progression, given that serum measurements collected as part of a prospective study in unsupplemented patients would likely reveal some subjects with B12 deficiency,” they concluded.
The authors declared no relevant disclosures. The study was supported by a grant from the Michael J. Fox Foundation for Parkinson’s Research, as well as privately donated grants.
SOURCE: Christine C et al. Movement Dis. 2018 Mar 6. doi: 10.1002/mds.27301.
FROM MOVEMENT DISORDERS
Key clinical point: Prevention or early correction of low B12 may potentially be a therapeutic target to slow progression in early Parkinson’s disease.
Main finding: Participants in the lowest B12 tertile developed greater morbidity with an annualized worsening of the ambulatory capacity score of 1.53, compared with 0.77 in patients in the upper tertile.
Study details: Analysis of vitamin B12 in 680 baseline and 456 follow-up serum samples of patients with PD participating in the double-blind, randomized DATATOP trial.
Disclosures: The authors declared no relevant disclosures. The study was supported by a grant from the Michael J. Fox Foundation for Parkinson’s Research, as well as privately donated grants.
Source: Christine C et al. Movement Dis. 2018 Mar 6. doi: 10.1002/mds.27301.