INTRODUCTION & AIMS: Alzheimer’s disease (AD) is the most common cause of dementia with age and s... more INTRODUCTION & AIMS: Alzheimer’s disease (AD) is the most common cause of dementia with age and specific genes as primary risk factors. The early detection of subjects at risk is a key priority. AIMS: (1) Develop a model using proton magnetic resonance spectroscopy (1H-MRS) to monitor clinical outcomes of carriers with a fully penetrant mutation that causes AD, and (2) Apply knowledge discovery algorithms to predict key biomarkers for AD diagnosis and monitoring. 1H-MRS is a non-invasive technique that evaluates brain chemistry in vivo – therefore this method provides an alternative to pre-clinical animal models of brain disease.
Studies performed in subtropical populations have found significant association between the pheno... more Studies performed in subtropical populations have found significant association between the phenotype multiple sclerosis (MS) and the major histocompatibility complex (MHC). We present the results of a case-control study conducted on a tropical population (Antioquia, Colombia) in order to detect a possible association between MS and HLA DQα (HLA DQA1*) alleles. Forty chromosomes belonging to MS patients were compared to two sets of controls (40 and 910 chromosomes, respectively). The HLA DQA1*0101 and DQA1*0102 alleles were found in a significantly higher proportion among the cases than among the controls, whereas the HLA DQA1*0103 allele was found in a significantly lower proportion of the cases. These results suggest that the association of HLA DQA1*0101, DQA1*0102 and DQA1*0103 to the MS phenotype found in Caucasian subtropical populations remains in individuals with MS inhabiting the tropics. This finding could mean that the major genetic component associated to the MHC in subtr...
Individuals affected with multiple sclerosis (MS) from a genetically homogeneous Caucasian popula... more Individuals affected with multiple sclerosis (MS) from a genetically homogeneous Caucasian population in Antioquia, a tropical region of Colombia, were evaluated in order to observe the clinical behavior of the disease. The frequency of clinical manifestations in 65 patients with definite MS from Antioquia was compared with those reported from temperate regions. The most common manifestations were optic neuritis and motor symptoms with absence of cerebellar symptoms. This presentation is significantly different from the frequency distribution at onset in series from temperate regions. These differences suggest that environmental factors could modify the clinical expression of MS in this population.
Background: Alzheimer's disease (AD) is the most common cause of dementia; the main risk factors ... more Background: Alzheimer's disease (AD) is the most common cause of dementia; the main risk factors are age and several recently identified genes. A major challenge for AD research is the early detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy (1 H-MRS), a noninvasive technique that evaluates brain chemistry in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD. Methods: We studied 75 subjects from the largest multigenerational pedigree in the world (w5000 people) that segregates a unique form of early-onset Alzheimer's disease (EOAD) caused by a fully penetrant mutation in the Presenilin-1 gene (PSEN1 p.Glu280Ala [E280 A]). Forty-four subjects were carriers of the mutation, and 31 were noncarriers. Seventeen carriers had either mild cognitive impairment (MCI) or early-stage AD (collectively MCI-AD). In right and left parietal white mater and parasagittal parietal gray matter (RPPGM and LPPGM) of the posterior cingulate gyrus and precuneus, we measured levels of the brain metabolites N-acetylaspartate (NAA), inositol (Ins), choline (Cho), and glutamate-glutamine complex (Glx) relative to creatine (Cr) levels (NAA/Cr, Ins/Cr, Cho/ Cr, and Glx/Cr, respectively) with two-dimensional 1 H-MRS. Using advanced recursive partition analysis and random forest analysis, we built classificatory decision trees for both mutation carrier status and the presence of MCI-AD symptoms, fitting them to 1 H-MRS data while controlling for age, educational level, and sex. Results: We found that (1) the combination of LPPGM Cho/Cr ,0.165 and RPPGM Glx/Cr .1.54 fully excluded carriers; (2) LPPGM Cho/Cr .0.165, RPPGM Glx/Cr ,1.54, and left parietal white mater NAA/Cr .1.16 identified asymptomatic carriers with sensitivity of 97.7% and specificity of 77.4%; and (3) RPPGM NAA/Cr .1.05 defined asymptomatic subjects (independent of carrier status) with sensitivity of 100% and a specificity of 96.6%. Conclusions: Brain metabolites measured by 1 H-MRS in the posterior cingulate gyrus and precuneus are optimally sensitive and specific potential noninvasive biomarkers of subclinical emergence of AD caused by the PSEN1 p.Glu280Ala (E280 A) mutation.
A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD. Molecular Psychiatry:E... more A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD. Molecular Psychiatry:Epub ahead of print. A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD
Discrimination and quantification of the environmental and genetic components involved in develop... more Discrimination and quantification of the environmental and genetic components involved in developing multiple sclerosis (MS) have not been made. In order to discriminate these components we have ascertained affected individuals by MS belonging to the Paisa community from Antioquia, Colombia, a state localized in the tropical area of South America, to detect eventual linkage disequilibrium to HLA, locus DQ alpha, which could demonstrate the relevance of the genetic component. A contingence analysis among case-control HLA DQ alpha genotype distributions, by using Monte Carlo resampling method to solve small number sample, showed that there are significant differences between the two groups. We observe that HLA DQ alpha 1.1, 1.2 allele frequencies were higher in the cases than in the controls. Also, there was significant HLA DQ alpha 3 allele lower frequency (p < 0.05) in the cases than in the controls. Similar results have been described in other Caucasian populations living in non...
To date, biomarkers based on nonconventional MRI have not been standardized for diagnosis and fol... more To date, biomarkers based on nonconventional MRI have not been standardized for diagnosis and follow-up of patients with multiple sclerosis (MS). The sequential monitoring of pathogenesis in MS by imaging of the normal appearing brain tissue is an important research tool in understanding the early stages of MS. In this review, we focus on the importance of deciphering the physiopatho-genesis of the disease cascade in vivo based on imaging biomarkers that allow a correlation with immunohistochemistry and molecular biology findings in order to provide earlier clinical diagnosis and better individualization of treatment and follow-up in patients with MS. Among the noncon-ventional imaging techniques available, we remark on the importance of proton magnetic resonance spectroscopy imaging because of its ability to assist in the simultaneous evaluation of different events in the pathogenesis of MS that cannot be determined by conventional MRI. Non-conventional MRI and the use of novel contrast agents are expected to elucidate the process of neuroinflammation and excitotoxicity in vivo that characterizes MS, thus leading to more specific neuroprotective and immunomodulatory therapies and reducing progression toward disability.
Background—Despite the current availability of disease modifying therapies for the treatment of m... more Background—Despite the current availability of disease modifying therapies for the treatment of multiple sclerosis, there are still patients who suffer from severe neurological dysfunction in the relapsing-remitting or early progressive forms of the disease. For these patients autologous hematopoietic stem cell transplant offers an important therapeutic solution to prevent progression to irreversible disability. In spite of multiple studies in the last two decades, patient inclusion criteria, protocols for peripheral blood stem cell mobilization and bone marrow cell conditioning and methodology of follow up for autologous hematopoietic stem cell transplant in multiple sclerosis have not been strictly unified.
Although no evidence of disease activity (NEDA) permits evaluation of response to treatment in th... more Although no evidence of disease activity (NEDA) permits evaluation of response to treatment in the systematic follow-up of patients with multiple sclerosis (MS), its ability to accomplish detection of surreptitious activity of disease is limited, thus being unable to prevent patients from falling into a non-reversible progressive phase of disease. A protocol of evaluation based on the use of validated biomarkers that is conducted at an early stage of disease would permit the capture of abnormal neuroimmunological phenomena and lead towards intervention with modifying therapy before tissue damage has been reached.
Background:Alzheimer’s disease (AD) is the most common cause of dementia; the main risk factors a... more Background:Alzheimer’s disease (AD) is the most common cause of dementia; the main risk factors are age and several recently identified genes. A major challenge for AD research is the early detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy ( 1 H-MRS), a noninvasive technique that evaluates brain chemistry in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD. Methods:We studied 75 subjects from the largest multigenerational pedigree in the world (w5000 people) that segregates a unique form of early-onset Alzheimer’s disease (EOAD) caused by a fully penetrant mutation in the Presenilin-1 gene (PSEN1p.Glu280Ala [E280 A]). Forty-four subjects were carriers of the mutation, and 31 were noncarriers. Seventeen carriers had either mild cognitive impairment (MCI) or early-stage AD (collectively MCI-AD). In right and left parietal white mater and parasagittal parietal gray matter (RPPGM and LPPGM) of the posterior cingulate gyrus and precuneus, we measured levels of the brain metabolites N-acetylaspartate (NAA), inositol (Ins), choline (Cho), and glutamate-glutamine complex (Glx) relative to creatine (Cr) levels (NAA/Cr, Ins/Cr, Cho/ Cr, and Glx/Cr, respectively) with two-dimensional 1 H-MRS. Using advanced recursive partition analysis and random forest analysis, we built classificatory decision trees for both mutation carrier status and the presence of MCI-AD symptoms, fitting them to 1 H-MRS data while controlling for age, educational level, and sex. Results:We found that (1) the combination of LPPGM Cho/Cr,0.165 and RPPGM Glx/Cr.1.54 fully excluded carriers; (2) LPPGM Cho/Cr.0.165, RPPGM Glx/Cr,1.54, and left parietal white mater NAA/Cr.1.16 identified asymptomatic carriers with sensitivity of 97.7% and specificity of 77.4%; and (3) RPPGM NAA/Cr.1.05 defined asymptomatic subjects (independent of carrier status) with sensitivity of 100% and a specificity of 96.6%. Conclusions:Brain metabolites measured by 1 H-MRS in the posterior cingulate gyrus and precuneus are optimally sensitive and specific potential noninvasive biomarkers of subclinical emergence of AD caused by thePSEN1p.Glu280Ala (E280 A) mutation. 2013 The Alzheimer’s Association. All rights reserved
To date, biomarkers based on nonconventional MRI have not been standardized for diagnosis and
fol... more To date, biomarkers based on nonconventional MRI have not been standardized for diagnosis and follow-up of patients with multiple sclerosis (MS). The sequential monitoring of pathogenesis in MS by imaging of the normal appearing brain tissue is an important research tool in understanding the early stages of MS. In this review, we focus on the importance of deciphering the physiopathogenesis of the disease cascade in vivo based on imaging biomarkers that allow a correlation with immunohistochemistry and molecular biology findings in order to provide earlier clinical diagnosis and better individualization of treatment and follow-up in patients with MS. Among the nonconventional imaging techniques available, we remark on the importance of proton magnetic resonance spectroscopy imaging because of its ability to assist in the simultaneous evaluation of different events in the pathogenesis of MS that cannot be determined by conventional MRI. Nonconventional MRI and the use of novel contrast agents are expected to elucidate the process of neuroinflammation and excitotoxicity in vivo that characterizes MS, thus leading to more specific neuroprotective and immunomodulatory therapies and reducing progression toward disability. Neurol Neuroimmunol Neuroinflamm2014;1:e45; doi: 10.1212/NXI.0000000000000045
Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting th... more Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a familybased design. Family-and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n = 6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.
INTRODUCTION & AIMS: Alzheimer’s disease (AD) is the most common cause of dementia with age and s... more INTRODUCTION & AIMS: Alzheimer’s disease (AD) is the most common cause of dementia with age and specific genes as primary risk factors. The early detection of subjects at risk is a key priority. AIMS: (1) Develop a model using proton magnetic resonance spectroscopy (1H-MRS) to monitor clinical outcomes of carriers with a fully penetrant mutation that causes AD, and (2) Apply knowledge discovery algorithms to predict key biomarkers for AD diagnosis and monitoring. 1H-MRS is a non-invasive technique that evaluates brain chemistry in vivo – therefore this method provides an alternative to pre-clinical animal models of brain disease.
Studies performed in subtropical populations have found significant association between the pheno... more Studies performed in subtropical populations have found significant association between the phenotype multiple sclerosis (MS) and the major histocompatibility complex (MHC). We present the results of a case-control study conducted on a tropical population (Antioquia, Colombia) in order to detect a possible association between MS and HLA DQα (HLA DQA1*) alleles. Forty chromosomes belonging to MS patients were compared to two sets of controls (40 and 910 chromosomes, respectively). The HLA DQA1*0101 and DQA1*0102 alleles were found in a significantly higher proportion among the cases than among the controls, whereas the HLA DQA1*0103 allele was found in a significantly lower proportion of the cases. These results suggest that the association of HLA DQA1*0101, DQA1*0102 and DQA1*0103 to the MS phenotype found in Caucasian subtropical populations remains in individuals with MS inhabiting the tropics. This finding could mean that the major genetic component associated to the MHC in subtr...
Individuals affected with multiple sclerosis (MS) from a genetically homogeneous Caucasian popula... more Individuals affected with multiple sclerosis (MS) from a genetically homogeneous Caucasian population in Antioquia, a tropical region of Colombia, were evaluated in order to observe the clinical behavior of the disease. The frequency of clinical manifestations in 65 patients with definite MS from Antioquia was compared with those reported from temperate regions. The most common manifestations were optic neuritis and motor symptoms with absence of cerebellar symptoms. This presentation is significantly different from the frequency distribution at onset in series from temperate regions. These differences suggest that environmental factors could modify the clinical expression of MS in this population.
Background: Alzheimer's disease (AD) is the most common cause of dementia; the main risk factors ... more Background: Alzheimer's disease (AD) is the most common cause of dementia; the main risk factors are age and several recently identified genes. A major challenge for AD research is the early detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy (1 H-MRS), a noninvasive technique that evaluates brain chemistry in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD. Methods: We studied 75 subjects from the largest multigenerational pedigree in the world (w5000 people) that segregates a unique form of early-onset Alzheimer's disease (EOAD) caused by a fully penetrant mutation in the Presenilin-1 gene (PSEN1 p.Glu280Ala [E280 A]). Forty-four subjects were carriers of the mutation, and 31 were noncarriers. Seventeen carriers had either mild cognitive impairment (MCI) or early-stage AD (collectively MCI-AD). In right and left parietal white mater and parasagittal parietal gray matter (RPPGM and LPPGM) of the posterior cingulate gyrus and precuneus, we measured levels of the brain metabolites N-acetylaspartate (NAA), inositol (Ins), choline (Cho), and glutamate-glutamine complex (Glx) relative to creatine (Cr) levels (NAA/Cr, Ins/Cr, Cho/ Cr, and Glx/Cr, respectively) with two-dimensional 1 H-MRS. Using advanced recursive partition analysis and random forest analysis, we built classificatory decision trees for both mutation carrier status and the presence of MCI-AD symptoms, fitting them to 1 H-MRS data while controlling for age, educational level, and sex. Results: We found that (1) the combination of LPPGM Cho/Cr ,0.165 and RPPGM Glx/Cr .1.54 fully excluded carriers; (2) LPPGM Cho/Cr .0.165, RPPGM Glx/Cr ,1.54, and left parietal white mater NAA/Cr .1.16 identified asymptomatic carriers with sensitivity of 97.7% and specificity of 77.4%; and (3) RPPGM NAA/Cr .1.05 defined asymptomatic subjects (independent of carrier status) with sensitivity of 100% and a specificity of 96.6%. Conclusions: Brain metabolites measured by 1 H-MRS in the posterior cingulate gyrus and precuneus are optimally sensitive and specific potential noninvasive biomarkers of subclinical emergence of AD caused by the PSEN1 p.Glu280Ala (E280 A) mutation.
A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD. Molecular Psychiatry:E... more A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD. Molecular Psychiatry:Epub ahead of print. A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD
Discrimination and quantification of the environmental and genetic components involved in develop... more Discrimination and quantification of the environmental and genetic components involved in developing multiple sclerosis (MS) have not been made. In order to discriminate these components we have ascertained affected individuals by MS belonging to the Paisa community from Antioquia, Colombia, a state localized in the tropical area of South America, to detect eventual linkage disequilibrium to HLA, locus DQ alpha, which could demonstrate the relevance of the genetic component. A contingence analysis among case-control HLA DQ alpha genotype distributions, by using Monte Carlo resampling method to solve small number sample, showed that there are significant differences between the two groups. We observe that HLA DQ alpha 1.1, 1.2 allele frequencies were higher in the cases than in the controls. Also, there was significant HLA DQ alpha 3 allele lower frequency (p < 0.05) in the cases than in the controls. Similar results have been described in other Caucasian populations living in non...
To date, biomarkers based on nonconventional MRI have not been standardized for diagnosis and fol... more To date, biomarkers based on nonconventional MRI have not been standardized for diagnosis and follow-up of patients with multiple sclerosis (MS). The sequential monitoring of pathogenesis in MS by imaging of the normal appearing brain tissue is an important research tool in understanding the early stages of MS. In this review, we focus on the importance of deciphering the physiopatho-genesis of the disease cascade in vivo based on imaging biomarkers that allow a correlation with immunohistochemistry and molecular biology findings in order to provide earlier clinical diagnosis and better individualization of treatment and follow-up in patients with MS. Among the noncon-ventional imaging techniques available, we remark on the importance of proton magnetic resonance spectroscopy imaging because of its ability to assist in the simultaneous evaluation of different events in the pathogenesis of MS that cannot be determined by conventional MRI. Non-conventional MRI and the use of novel contrast agents are expected to elucidate the process of neuroinflammation and excitotoxicity in vivo that characterizes MS, thus leading to more specific neuroprotective and immunomodulatory therapies and reducing progression toward disability.
Background—Despite the current availability of disease modifying therapies for the treatment of m... more Background—Despite the current availability of disease modifying therapies for the treatment of multiple sclerosis, there are still patients who suffer from severe neurological dysfunction in the relapsing-remitting or early progressive forms of the disease. For these patients autologous hematopoietic stem cell transplant offers an important therapeutic solution to prevent progression to irreversible disability. In spite of multiple studies in the last two decades, patient inclusion criteria, protocols for peripheral blood stem cell mobilization and bone marrow cell conditioning and methodology of follow up for autologous hematopoietic stem cell transplant in multiple sclerosis have not been strictly unified.
Although no evidence of disease activity (NEDA) permits evaluation of response to treatment in th... more Although no evidence of disease activity (NEDA) permits evaluation of response to treatment in the systematic follow-up of patients with multiple sclerosis (MS), its ability to accomplish detection of surreptitious activity of disease is limited, thus being unable to prevent patients from falling into a non-reversible progressive phase of disease. A protocol of evaluation based on the use of validated biomarkers that is conducted at an early stage of disease would permit the capture of abnormal neuroimmunological phenomena and lead towards intervention with modifying therapy before tissue damage has been reached.
Background:Alzheimer’s disease (AD) is the most common cause of dementia; the main risk factors a... more Background:Alzheimer’s disease (AD) is the most common cause of dementia; the main risk factors are age and several recently identified genes. A major challenge for AD research is the early detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy ( 1 H-MRS), a noninvasive technique that evaluates brain chemistry in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD. Methods:We studied 75 subjects from the largest multigenerational pedigree in the world (w5000 people) that segregates a unique form of early-onset Alzheimer’s disease (EOAD) caused by a fully penetrant mutation in the Presenilin-1 gene (PSEN1p.Glu280Ala [E280 A]). Forty-four subjects were carriers of the mutation, and 31 were noncarriers. Seventeen carriers had either mild cognitive impairment (MCI) or early-stage AD (collectively MCI-AD). In right and left parietal white mater and parasagittal parietal gray matter (RPPGM and LPPGM) of the posterior cingulate gyrus and precuneus, we measured levels of the brain metabolites N-acetylaspartate (NAA), inositol (Ins), choline (Cho), and glutamate-glutamine complex (Glx) relative to creatine (Cr) levels (NAA/Cr, Ins/Cr, Cho/ Cr, and Glx/Cr, respectively) with two-dimensional 1 H-MRS. Using advanced recursive partition analysis and random forest analysis, we built classificatory decision trees for both mutation carrier status and the presence of MCI-AD symptoms, fitting them to 1 H-MRS data while controlling for age, educational level, and sex. Results:We found that (1) the combination of LPPGM Cho/Cr,0.165 and RPPGM Glx/Cr.1.54 fully excluded carriers; (2) LPPGM Cho/Cr.0.165, RPPGM Glx/Cr,1.54, and left parietal white mater NAA/Cr.1.16 identified asymptomatic carriers with sensitivity of 97.7% and specificity of 77.4%; and (3) RPPGM NAA/Cr.1.05 defined asymptomatic subjects (independent of carrier status) with sensitivity of 100% and a specificity of 96.6%. Conclusions:Brain metabolites measured by 1 H-MRS in the posterior cingulate gyrus and precuneus are optimally sensitive and specific potential noninvasive biomarkers of subclinical emergence of AD caused by thePSEN1p.Glu280Ala (E280 A) mutation. 2013 The Alzheimer’s Association. All rights reserved
To date, biomarkers based on nonconventional MRI have not been standardized for diagnosis and
fol... more To date, biomarkers based on nonconventional MRI have not been standardized for diagnosis and follow-up of patients with multiple sclerosis (MS). The sequential monitoring of pathogenesis in MS by imaging of the normal appearing brain tissue is an important research tool in understanding the early stages of MS. In this review, we focus on the importance of deciphering the physiopathogenesis of the disease cascade in vivo based on imaging biomarkers that allow a correlation with immunohistochemistry and molecular biology findings in order to provide earlier clinical diagnosis and better individualization of treatment and follow-up in patients with MS. Among the nonconventional imaging techniques available, we remark on the importance of proton magnetic resonance spectroscopy imaging because of its ability to assist in the simultaneous evaluation of different events in the pathogenesis of MS that cannot be determined by conventional MRI. Nonconventional MRI and the use of novel contrast agents are expected to elucidate the process of neuroinflammation and excitotoxicity in vivo that characterizes MS, thus leading to more specific neuroprotective and immunomodulatory therapies and reducing progression toward disability. Neurol Neuroimmunol Neuroinflamm2014;1:e45; doi: 10.1212/NXI.0000000000000045
Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting th... more Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a familybased design. Family-and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n = 6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.
Uploads
Papers by A. C Londoño
detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy (
1
H-MRS), a noninvasive technique that evaluates brain chemistry
in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD.
Methods:We studied 75 subjects from the largest multigenerational pedigree in the world (w5000
people) that segregates a unique form of early-onset Alzheimer’s disease (EOAD) caused by a fully
penetrant mutation in the Presenilin-1 gene (PSEN1p.Glu280Ala [E280 A]). Forty-four subjects
were carriers of the mutation, and 31 were noncarriers. Seventeen carriers had either mild cognitive
impairment (MCI) or early-stage AD (collectively MCI-AD). In right and left parietal white mater
and parasagittal parietal gray matter (RPPGM and LPPGM) of the posterior cingulate gyrus and precuneus, we measured levels of the brain metabolites N-acetylaspartate (NAA), inositol (Ins), choline
(Cho), and glutamate-glutamine complex (Glx) relative to creatine (Cr) levels (NAA/Cr, Ins/Cr, Cho/
Cr, and Glx/Cr, respectively) with two-dimensional
1
H-MRS. Using advanced recursive partition
analysis and random forest analysis, we built classificatory decision trees for both mutation carrier
status and the presence of MCI-AD symptoms, fitting them to
1
H-MRS data while controlling for
age, educational level, and sex.
Results:We found that (1) the combination of LPPGM Cho/Cr,0.165 and RPPGM Glx/Cr.1.54
fully excluded carriers; (2) LPPGM Cho/Cr.0.165, RPPGM Glx/Cr,1.54, and left parietal white
mater NAA/Cr.1.16 identified asymptomatic carriers with sensitivity of 97.7% and specificity of
77.4%; and (3) RPPGM NAA/Cr.1.05 defined asymptomatic subjects (independent of carrier status) with sensitivity of 100% and a specificity of 96.6%.
Conclusions:Brain metabolites measured by
1
H-MRS in the posterior cingulate gyrus and precuneus are optimally sensitive and specific potential noninvasive biomarkers of subclinical emergence
of AD caused by thePSEN1p.Glu280Ala (E280 A) mutation. 2013 The Alzheimer’s Association. All rights reserved
follow-up of patients with multiple sclerosis (MS). The sequential monitoring of pathogenesis in
MS by imaging of the normal appearing brain tissue is an important research tool in understanding
the early stages of MS. In this review, we focus on the importance of deciphering the physiopathogenesis of the disease cascade in vivo based on imaging biomarkers that allow a correlation with
immunohistochemistry and molecular biology findings in order to provide earlier clinical diagnosis
and better individualization of treatment and follow-up in patients with MS. Among the nonconventional imaging techniques available, we remark on the importance of proton magnetic resonance spectroscopy imaging because of its ability to assist in the simultaneous evaluation of
different events in the pathogenesis of MS that cannot be determined by conventional MRI. Nonconventional MRI and the use of novel contrast agents are expected to elucidate the process of
neuroinflammation and excitotoxicity in vivo that characterizes MS, thus leading to more specific
neuroprotective and immunomodulatory therapies and reducing progression toward disability.
Neurol Neuroimmunol Neuroinflamm2014;1:e45; doi: 10.1212/NXI.0000000000000045
detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy (
1
H-MRS), a noninvasive technique that evaluates brain chemistry
in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD.
Methods:We studied 75 subjects from the largest multigenerational pedigree in the world (w5000
people) that segregates a unique form of early-onset Alzheimer’s disease (EOAD) caused by a fully
penetrant mutation in the Presenilin-1 gene (PSEN1p.Glu280Ala [E280 A]). Forty-four subjects
were carriers of the mutation, and 31 were noncarriers. Seventeen carriers had either mild cognitive
impairment (MCI) or early-stage AD (collectively MCI-AD). In right and left parietal white mater
and parasagittal parietal gray matter (RPPGM and LPPGM) of the posterior cingulate gyrus and precuneus, we measured levels of the brain metabolites N-acetylaspartate (NAA), inositol (Ins), choline
(Cho), and glutamate-glutamine complex (Glx) relative to creatine (Cr) levels (NAA/Cr, Ins/Cr, Cho/
Cr, and Glx/Cr, respectively) with two-dimensional
1
H-MRS. Using advanced recursive partition
analysis and random forest analysis, we built classificatory decision trees for both mutation carrier
status and the presence of MCI-AD symptoms, fitting them to
1
H-MRS data while controlling for
age, educational level, and sex.
Results:We found that (1) the combination of LPPGM Cho/Cr,0.165 and RPPGM Glx/Cr.1.54
fully excluded carriers; (2) LPPGM Cho/Cr.0.165, RPPGM Glx/Cr,1.54, and left parietal white
mater NAA/Cr.1.16 identified asymptomatic carriers with sensitivity of 97.7% and specificity of
77.4%; and (3) RPPGM NAA/Cr.1.05 defined asymptomatic subjects (independent of carrier status) with sensitivity of 100% and a specificity of 96.6%.
Conclusions:Brain metabolites measured by
1
H-MRS in the posterior cingulate gyrus and precuneus are optimally sensitive and specific potential noninvasive biomarkers of subclinical emergence
of AD caused by thePSEN1p.Glu280Ala (E280 A) mutation. 2013 The Alzheimer’s Association. All rights reserved
follow-up of patients with multiple sclerosis (MS). The sequential monitoring of pathogenesis in
MS by imaging of the normal appearing brain tissue is an important research tool in understanding
the early stages of MS. In this review, we focus on the importance of deciphering the physiopathogenesis of the disease cascade in vivo based on imaging biomarkers that allow a correlation with
immunohistochemistry and molecular biology findings in order to provide earlier clinical diagnosis
and better individualization of treatment and follow-up in patients with MS. Among the nonconventional imaging techniques available, we remark on the importance of proton magnetic resonance spectroscopy imaging because of its ability to assist in the simultaneous evaluation of
different events in the pathogenesis of MS that cannot be determined by conventional MRI. Nonconventional MRI and the use of novel contrast agents are expected to elucidate the process of
neuroinflammation and excitotoxicity in vivo that characterizes MS, thus leading to more specific
neuroprotective and immunomodulatory therapies and reducing progression toward disability.
Neurol Neuroimmunol Neuroinflamm2014;1:e45; doi: 10.1212/NXI.0000000000000045