Tienda online donde Comprar Clinical neurophysiology of the vestibular systen al precio 118,40 € ... more Tienda online donde Comprar Clinical neurophysiology of the vestibular systen al precio 118,40 € de Robert Baloh, tienda de Libros de Medicina, Libros de Otorrinolaringologia - Audiologia
The clinical presentation of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disea... more The clinical presentation of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, varies widely across patients, making it challenging to determine if potential therapeutics slow progression. We sought to determine whether there were common patterns of disease progression that could aid in the design and analysis of clinical trials. We developed an approach based on a mixture of Gaussian processes to identify clusters of patients sharing similar disease progression patterns, modeling their average trajectories and the variability in each cluster. We show that ALS progression is frequently nonlinear, with periods of stable disease preceded or followed by rapid decline. We also show that our approach can be extended to Alzheimer’s and Parkinson’s diseases. Our results advance the characterization of disease progression of ALS and provide a flexible modeling approach that can be applied to other progressive diseases.
Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patien... more Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot–Marie–Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragm...
Answer ALS is a biological and clinical resource of patient-derived, induced pluripotent stem (iP... more Answer ALS is a biological and clinical resource of patient-derived, induced pluripotent stem (iPS) cell lines, multi-omic data derived from iPS neurons and longitudinal clinical and smartphone data from over 1,000 patients with ALS. This resource provides population-level biological and clinical data that may be employed to identify clinical–molecular–biochemical subtypes of amyotrophic lateral sclerosis (ALS). A unique smartphone-based system was employed to collect deep clinical data, including fine motor activity, speech, breathing and linguistics/cognition. The iPS spinal neurons were blood derived from each patient and these cells underwent multi-omic analytics including whole-genome sequencing, RNA transcriptomics, ATAC-sequencing and proteomics. The intent of these data is for the generation of integrated clinical and biological signatures using bioinformatics, statistics and computational biology to establish patterns that may lead to a better understanding of the underlyin...
University of California, Irvine, CA, USA, Massachusetts General Hospital, Boston, MA, USA, Unive... more University of California, Irvine, CA, USA, Massachusetts General Hospital, Boston, MA, USA, University of Massachusetts Medical School, Worcester, Massachusetts, USA, Mayo Clinic, Rochester, MN, USA, California Pacific Medical Center, San Francisco, CA, USA, Cedars-Sinai Medical Center, Los Angeles, CA, USA, Brainstorm Cell Therapeutics, New York, NY, USA, Brainstorm Cell Therapeutics, Petach Tikva, Israel, Porterhouse Medical, King of Prussia, PA, USA
An unbiased stereological method was used to assess the effect of aging on the number of neurons ... more An unbiased stereological method was used to assess the effect of aging on the number of neurons in the human medial vestibular nucleus. We studied 13 normal brainstem specimens (age at death from 40 to 93 years) that were part of a prior study that counted neuronal profiles and used a correction factor to estimate the number of neurons in the human vestibular nucleus. On average, we found 151 · 10 3 ( CV = 0.15) neurons in the medial vestibular nucleus, which is 18% significant decrease in the number of neurons with aging. This age-related neuronal loss in the vestibular nucleus could have important functional implications regarding the well-known deterioration in balance that occurs with aging.
We measured the horizontal linear vestibulo-ocular reflex (LVOR) in normal human subjects and pat... more We measured the horizontal linear vestibulo-ocular reflex (LVOR) in normal human subjects and patients with abnormal angular vestibulo-ocular reflexes (AVOR) and abnormal smooth pursuit. Eye movements were induced by sinusoidal linear acceleration along the interaural axis (0.8 Hz, 0.5 g peak acceleration) on a parallel swing. Horizontal movement of each eye was recorded with an infrared limbus tracking device. Normal subjects increased LVOR sensitivity as real or imagined targets moved closer. Perceived target distance was more important than the vergence angle since changing the vergence angle alone with prisms resulted in only a slight change in LVOR sensitivity. Subjects suppressed the LVOR with real or imagined head-fixed targets. Patients with decreased horizontal AVOR responses had decreased horizontal LVOR responses with imagined earth-fixed targets in the dark. They were able to generate normal velocity LVOR responses with real earth-fixed targets. Patients with increased A...
While most studies have demonstrated damage to the cochlear and vestibular endorgan as the primar... more While most studies have demonstrated damage to the cochlear and vestibular endorgan as the primary site of aminoglycoside toxicity, the effect on the primary afferent neurons of the vestibular ganglion remains to be determined. This study used the unbiased stereology-optical fractionator method to obtain estimates of the vestibular ganglion neuronal number. Archival temporal bone specimens from seven subjects with a history of gentamicin (n = 3) and streptomycin (n = 4) aminoglycoside ototoxicity were used. The post-ototoxicity survival time ranged from two months to 8 years, with an average of 2.2 years. Seven archival human temporal bone specimens from age-matched subjects with no history of audiovestibular symptoms or ototoxicity served as controls. Group means were compared using unpaired, two-tailed student's t test. The average vestibular ganglion neuronal number in the aminoglycoside ototoxicity group was 20, 733 neurons (CV = 0.073), which was significantly lower (p <...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for pert...
Degenerative changes during aging have been identified in the inner ear and in the vestibular ner... more Degenerative changes during aging have been identified in the inner ear and in the vestibular nerve, but not in the human vestibular nuclear complex (VNC). Therefore, the purpose of this study was to document quantitative morphometric changes within the VNC in humans as a function of age. The VNC of normal human subjects was examined for age-related changes using computer-based microscopy. Neuronal counts, nuclear volume, neuronal density, and nuclear length of the 4 vestibular nuclei were determined in 15 normal people, age 40 to 93 years. Based on a linear model, there was approximately a 3% neuronal loss per decade from age forty to ninety. VNC volume and neuronal density also decreased significantly with age, although to a lesser degree than did the number of neurons. Neuronal loss as a percentage of the total number of neurons was greatest in the superior vestibular nucleus and least in the medial vestibular nucleus. Despite the overall loss of neurons, the number of giant neur...
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the pro... more Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several inherited pathogenic mutations have been identified as causative, the vast majority of cases are sporadic with no family history of disease. Thus, for the majority of ALS cases, a specific causal abnormality is not known and the disease may be a product of multiple inter-related pathways contributing to varying degrees in different ALS patients. Using unsupervised machine learning algorithms, we stratified the transcriptomes of 148 ALS decedent cortex tissue samples into three distinct and robust molecular subtypes. The largest cluster, identified in 61% of patient samples, displayed hallmarks of oxidative and proteotoxic stress. Another 20% of the ALS patient samples exhibited high levels of retrotransposon expression and other signatures of TDP-43 dysfunction. Finally, a third group showed predominant signatures of glial activation (19%). T...
1. Horizontal and vertical eye movements were induced in normal human subjects by sinusoidal line... more 1. Horizontal and vertical eye movements were induced in normal human subjects by sinusoidal linear acceleration on a parallel swing. The swing frequency was 0.3 Hz and the peak horizontal and vertical acceleration ranged from 0.17 to 0.48 and 0.03 to 0.34 g, respectively. Eye movements were recorded with the scleral search coil technique. 2. With the subjects seated in the dark to stimulate the otolith-ocular reflex, swing displacement along the interaural axis induced horizontal eye movements with a mean sensitivity to translation (ST) (peak eye velocity/peak swing velocity) of 3.8 to 4.7 degrees/m and a mean phase shift (eye velocity re swing velocity) of -152 to -160 degrees. Vertical eye movements had ST and phase values comparable to those of the horizontal eye movements. When the subjects sat facing forward so that the horizontal linear accelerations occurred in the occipitonasal axis, almost identical vertical but no consistent horizontal eye movements were induced. In each ...
Annals of clinical and translational neurology, 2018
To investigate transplantation of rat Schwann cells or human iPSC-derived neural crest cells and ... more To investigate transplantation of rat Schwann cells or human iPSC-derived neural crest cells and derivatives into models of acquired and inherited peripheral myelin damage. Primary cultured rat Schwann cells labeled with a fluorescent protein for monitoring at various times after transplantation. Human-induced pluripotent stem cells (iPSCs) were differentiated into neural crest stem cells, and subsequently toward a Schwann cell lineage via two different protocols. Cell types were characterized using flow cytometry, immunocytochemistry, and transcriptomics. Rat Schwann cells and human iPSC derivatives were transplanted into (1) nude rats pretreated with lysolecithin to induce demyelination or (2) a transgenic rat model of dysmyelination due to PMP22 overexpression. Rat Schwann cells transplanted into sciatic nerves with either toxic demyelination or genetic dysmyelination engrafted successfully, and migrated longitudinally for relatively long distances, with more limited axial migrat...
Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular traffick... more Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A). We showed that MFN2 activity can be determined by Met and His interactions with Asp and Leu and controlled by PINK1 kinase-mediated phosphorylation of adjacent MFN2 Ser Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 Arg→Gln and MFN2 Thr→Met, as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr→Met mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynam...
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried ... more To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis o...
Objective:Amyotrophic lateral sclerosis (ALS) progresses at different rates between patients, mak... more Objective:Amyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression.Methods:A large cohort of patients was used to assess decline in muscle strength in right and left limbs over time using 2 different methods: The Tufts Quantitative Neuromuscular Exam and Accurate Test of Limb Isometric Strength protocol. Then advanced linear regression statistical methods were applied to assess progression rates in each limb.Results:This report shows that linearized progression models can predict general slopes of decline with good accuracy. Critically, the data demonst...
Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, ret... more Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1, which was termed 'retinal vasculopathy with cerebral leukodystrophy'. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different TREX1 mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhance...
Tienda online donde Comprar Clinical neurophysiology of the vestibular systen al precio 118,40 € ... more Tienda online donde Comprar Clinical neurophysiology of the vestibular systen al precio 118,40 € de Robert Baloh, tienda de Libros de Medicina, Libros de Otorrinolaringologia - Audiologia
The clinical presentation of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disea... more The clinical presentation of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, varies widely across patients, making it challenging to determine if potential therapeutics slow progression. We sought to determine whether there were common patterns of disease progression that could aid in the design and analysis of clinical trials. We developed an approach based on a mixture of Gaussian processes to identify clusters of patients sharing similar disease progression patterns, modeling their average trajectories and the variability in each cluster. We show that ALS progression is frequently nonlinear, with periods of stable disease preceded or followed by rapid decline. We also show that our approach can be extended to Alzheimer’s and Parkinson’s diseases. Our results advance the characterization of disease progression of ALS and provide a flexible modeling approach that can be applied to other progressive diseases.
Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patien... more Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot–Marie–Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragm...
Answer ALS is a biological and clinical resource of patient-derived, induced pluripotent stem (iP... more Answer ALS is a biological and clinical resource of patient-derived, induced pluripotent stem (iPS) cell lines, multi-omic data derived from iPS neurons and longitudinal clinical and smartphone data from over 1,000 patients with ALS. This resource provides population-level biological and clinical data that may be employed to identify clinical–molecular–biochemical subtypes of amyotrophic lateral sclerosis (ALS). A unique smartphone-based system was employed to collect deep clinical data, including fine motor activity, speech, breathing and linguistics/cognition. The iPS spinal neurons were blood derived from each patient and these cells underwent multi-omic analytics including whole-genome sequencing, RNA transcriptomics, ATAC-sequencing and proteomics. The intent of these data is for the generation of integrated clinical and biological signatures using bioinformatics, statistics and computational biology to establish patterns that may lead to a better understanding of the underlyin...
University of California, Irvine, CA, USA, Massachusetts General Hospital, Boston, MA, USA, Unive... more University of California, Irvine, CA, USA, Massachusetts General Hospital, Boston, MA, USA, University of Massachusetts Medical School, Worcester, Massachusetts, USA, Mayo Clinic, Rochester, MN, USA, California Pacific Medical Center, San Francisco, CA, USA, Cedars-Sinai Medical Center, Los Angeles, CA, USA, Brainstorm Cell Therapeutics, New York, NY, USA, Brainstorm Cell Therapeutics, Petach Tikva, Israel, Porterhouse Medical, King of Prussia, PA, USA
An unbiased stereological method was used to assess the effect of aging on the number of neurons ... more An unbiased stereological method was used to assess the effect of aging on the number of neurons in the human medial vestibular nucleus. We studied 13 normal brainstem specimens (age at death from 40 to 93 years) that were part of a prior study that counted neuronal profiles and used a correction factor to estimate the number of neurons in the human vestibular nucleus. On average, we found 151 · 10 3 ( CV = 0.15) neurons in the medial vestibular nucleus, which is 18% significant decrease in the number of neurons with aging. This age-related neuronal loss in the vestibular nucleus could have important functional implications regarding the well-known deterioration in balance that occurs with aging.
We measured the horizontal linear vestibulo-ocular reflex (LVOR) in normal human subjects and pat... more We measured the horizontal linear vestibulo-ocular reflex (LVOR) in normal human subjects and patients with abnormal angular vestibulo-ocular reflexes (AVOR) and abnormal smooth pursuit. Eye movements were induced by sinusoidal linear acceleration along the interaural axis (0.8 Hz, 0.5 g peak acceleration) on a parallel swing. Horizontal movement of each eye was recorded with an infrared limbus tracking device. Normal subjects increased LVOR sensitivity as real or imagined targets moved closer. Perceived target distance was more important than the vergence angle since changing the vergence angle alone with prisms resulted in only a slight change in LVOR sensitivity. Subjects suppressed the LVOR with real or imagined head-fixed targets. Patients with decreased horizontal AVOR responses had decreased horizontal LVOR responses with imagined earth-fixed targets in the dark. They were able to generate normal velocity LVOR responses with real earth-fixed targets. Patients with increased A...
While most studies have demonstrated damage to the cochlear and vestibular endorgan as the primar... more While most studies have demonstrated damage to the cochlear and vestibular endorgan as the primary site of aminoglycoside toxicity, the effect on the primary afferent neurons of the vestibular ganglion remains to be determined. This study used the unbiased stereology-optical fractionator method to obtain estimates of the vestibular ganglion neuronal number. Archival temporal bone specimens from seven subjects with a history of gentamicin (n = 3) and streptomycin (n = 4) aminoglycoside ototoxicity were used. The post-ototoxicity survival time ranged from two months to 8 years, with an average of 2.2 years. Seven archival human temporal bone specimens from age-matched subjects with no history of audiovestibular symptoms or ototoxicity served as controls. Group means were compared using unpaired, two-tailed student's t test. The average vestibular ganglion neuronal number in the aminoglycoside ototoxicity group was 20, 733 neurons (CV = 0.073), which was significantly lower (p <...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for pert...
Degenerative changes during aging have been identified in the inner ear and in the vestibular ner... more Degenerative changes during aging have been identified in the inner ear and in the vestibular nerve, but not in the human vestibular nuclear complex (VNC). Therefore, the purpose of this study was to document quantitative morphometric changes within the VNC in humans as a function of age. The VNC of normal human subjects was examined for age-related changes using computer-based microscopy. Neuronal counts, nuclear volume, neuronal density, and nuclear length of the 4 vestibular nuclei were determined in 15 normal people, age 40 to 93 years. Based on a linear model, there was approximately a 3% neuronal loss per decade from age forty to ninety. VNC volume and neuronal density also decreased significantly with age, although to a lesser degree than did the number of neurons. Neuronal loss as a percentage of the total number of neurons was greatest in the superior vestibular nucleus and least in the medial vestibular nucleus. Despite the overall loss of neurons, the number of giant neur...
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the pro... more Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several inherited pathogenic mutations have been identified as causative, the vast majority of cases are sporadic with no family history of disease. Thus, for the majority of ALS cases, a specific causal abnormality is not known and the disease may be a product of multiple inter-related pathways contributing to varying degrees in different ALS patients. Using unsupervised machine learning algorithms, we stratified the transcriptomes of 148 ALS decedent cortex tissue samples into three distinct and robust molecular subtypes. The largest cluster, identified in 61% of patient samples, displayed hallmarks of oxidative and proteotoxic stress. Another 20% of the ALS patient samples exhibited high levels of retrotransposon expression and other signatures of TDP-43 dysfunction. Finally, a third group showed predominant signatures of glial activation (19%). T...
1. Horizontal and vertical eye movements were induced in normal human subjects by sinusoidal line... more 1. Horizontal and vertical eye movements were induced in normal human subjects by sinusoidal linear acceleration on a parallel swing. The swing frequency was 0.3 Hz and the peak horizontal and vertical acceleration ranged from 0.17 to 0.48 and 0.03 to 0.34 g, respectively. Eye movements were recorded with the scleral search coil technique. 2. With the subjects seated in the dark to stimulate the otolith-ocular reflex, swing displacement along the interaural axis induced horizontal eye movements with a mean sensitivity to translation (ST) (peak eye velocity/peak swing velocity) of 3.8 to 4.7 degrees/m and a mean phase shift (eye velocity re swing velocity) of -152 to -160 degrees. Vertical eye movements had ST and phase values comparable to those of the horizontal eye movements. When the subjects sat facing forward so that the horizontal linear accelerations occurred in the occipitonasal axis, almost identical vertical but no consistent horizontal eye movements were induced. In each ...
Annals of clinical and translational neurology, 2018
To investigate transplantation of rat Schwann cells or human iPSC-derived neural crest cells and ... more To investigate transplantation of rat Schwann cells or human iPSC-derived neural crest cells and derivatives into models of acquired and inherited peripheral myelin damage. Primary cultured rat Schwann cells labeled with a fluorescent protein for monitoring at various times after transplantation. Human-induced pluripotent stem cells (iPSCs) were differentiated into neural crest stem cells, and subsequently toward a Schwann cell lineage via two different protocols. Cell types were characterized using flow cytometry, immunocytochemistry, and transcriptomics. Rat Schwann cells and human iPSC derivatives were transplanted into (1) nude rats pretreated with lysolecithin to induce demyelination or (2) a transgenic rat model of dysmyelination due to PMP22 overexpression. Rat Schwann cells transplanted into sciatic nerves with either toxic demyelination or genetic dysmyelination engrafted successfully, and migrated longitudinally for relatively long distances, with more limited axial migrat...
Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular traffick... more Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A). We showed that MFN2 activity can be determined by Met and His interactions with Asp and Leu and controlled by PINK1 kinase-mediated phosphorylation of adjacent MFN2 Ser Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 Arg→Gln and MFN2 Thr→Met, as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr→Met mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynam...
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried ... more To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis o...
Objective:Amyotrophic lateral sclerosis (ALS) progresses at different rates between patients, mak... more Objective:Amyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression.Methods:A large cohort of patients was used to assess decline in muscle strength in right and left limbs over time using 2 different methods: The Tufts Quantitative Neuromuscular Exam and Accurate Test of Limb Isometric Strength protocol. Then advanced linear regression statistical methods were applied to assess progression rates in each limb.Results:This report shows that linearized progression models can predict general slopes of decline with good accuracy. Critically, the data demonst...
Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, ret... more Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1, which was termed 'retinal vasculopathy with cerebral leukodystrophy'. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different TREX1 mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhance...
Uploads
Papers