A5074587216- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Parkinson's Disease Mechanisms and Treatments
- Prion Diseases and Protein Misfolding
- Cellular transport and secretion
- Nerve injury and regeneration
- Microtubule and mitosis dynamics
- Autoimmune Neurological Disorders and Treatments
- Cerebral Palsy and Movement Disorders
- Drug-Induced Ocular Toxicity
- Head and Neck Surgical Oncology
- Congenital Ear and Nasal Anomalies
- Ubiquitin and proteasome pathways
- CNS Lymphoma Diagnosis and Treatment
- Macrophage Migration Inhibitory Factor
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Neurological diseases and metabolism
- Diabetes and associated disorders
- Intracerebral and Subarachnoid Hemorrhage Research
- Signaling Pathways in Disease
- Genetics and Neurodevelopmental Disorders
- Venous Thromboembolism Diagnosis and Management
- Hereditary Neurological Disorders
- Glycogen Storage Diseases and Myoclonus
- Axon Guidance and Neuronal Signaling
Massachusetts General Hospital
2015-2024
Biogen (United States)
2021-2024
Amyotrophic Lateral Sclerosis Association
2007-2024
Harvard University
2012-2022
Clinical Research Institute
2019
Howard Hughes Medical Institute
2012-2018
Boston Children's Hospital
2013-2018
Brigham and Women's Hospital
2015-2017
The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated mutations SOD1 (SOD1 ALS).
Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes ALS has made it difficult to target upstream biological mechanisms disease, therapeutic interventions are usually administered relatively late in course Genetic forms offer unique opportunity for development, as genetic associations may reveal potential insights into disease etiology. also be amenable investigating...
We generated a knockout mouse for the neuronal-specific β-tubulin isoform Tubb3 to investigate its role in nervous system formation and maintenance.
Missense mutations in TUBB3, the gene that encodes neuronal-specific protein β-tubulin isotype 3, can cause isolated or syndromic congenital fibrosis of extraocular muscles, a form complex strabismus characterized by cranial nerve misguidance. One eight TUBB3 reported to c.1228G>A results E410K amino acid substitution directly alters kinesin motor binding site. We report detailed phenotypes unrelated individuals who harbour this de novo mutation, and thus define 'TUBB3 syndrome'. Individuals...
Microtubules are essential components of axon guidance machinery. Among β-tubulin mutations, only those in TUBB3 have been shown to cause primary errors guidance. All identified mutations TUBB2B result polymicrogyria, but it remains unclear whether can dysinnervation as a phenotype. We novel inherited heterozygous missense mutation that results an E421K amino acid substitution family who segregates congenital fibrosis the extraocular muscles (CFEOM) with polymicrogyria. Diffusion tensor...
Abstract Our objective was to determine whether modafinil alleviates fatigue in patients with amyotrophic lateral sclerosis (ALS). A placebo controlled trial a 3:1 modafinil:placebo randomization doses up 300 mg/day for 4 weeks followed by 8 of open maintenance treatment. The primary endpoint the Clinical Global Impressions‐Improvement Scale. Secondary endpoints were Fatigue Severity Scale, Epworth Sleepiness Beck Depression Inventory, Role Function and visual analog scales. Analysis...
Ibudilast (MN-166) is an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterases 3,4,10 11 (Gibson et al., 2006; Cho 2010). attenuates CNS microglial activation secretion pro-inflammatory cytokines (Fujimoto 1999; In vitro evidence suggests that ibudilast neuroprotective by suppressing neuronal cell death induced activation. People with ALS have increased measured [11C]PBR28-PET in the motor cortices. The primary objective to determine impact on reducing glial...
Neuroinflammation has been implicated in amyotrophic lateral sclerosis (ALS) and can be visualized using translocator protein (TSPO) radioligands. To become a reliable pharmacodynamic biomarker for ALS multicenter trials, TSPO radioligands have some challenges to overcome. We aimed investigate whether data pooling of different tracers (<sup>11</sup>C-PBR28 <sup>18</sup>F-DPA714) is feasible, after validation an established <sup>11</sup>C-PBR28 PET pseudo reference analysis technique...
Test the feasibility, adherence rates and optimal frequency of digital, remote assessments using ALSFRS-RSE via a customized smartphone-based app.
Objective: This study characterized two patient-reported outcome measures (PROMs): a patient-facing adaptation of the revised amyotrophic lateral sclerosis (ALS) Functional Rating Scale ("self-entry ALSFRS-R") and Activities-specific Balance Confidence (ABC) Scale. Methods: ALS patients presenting to clinic completed PROMs that included (1) self-entry ALSFRS-R, (2) (ABC Scale), (3) question about falls. PROM data were compared one another traditional ALSFRS-R collected by trained evaluators...
A heterozygous de novo c.1228G>A mutation (E410K) in the TUBB3 gene encoding neuronal-specific β-tubulin isotype 3 (TUBB3) causes E410K syndrome characterized by congenital fibrosis of extraocular muscles (CFEOM), facial weakness, intellectual and social disabilities, Kallmann (anosmia with hypogonadotropic hypogonadism). All subjects reported to date are sporadic cases.This study aimed report clinical, genetic, molecular features a familial presentation syndrome.Case mother three affected...
Different forms of cell transplantation therapy are being tested in models ALS. While the approach offers hope to patients with ALS, much still needs be learned laboratory before it is ready for human trials. Nevertheless, clinics across world offer various types open label high fees. We report a woman who received an injection into each frontal lobe Beijing, China. Her ALS progressed at more rapid rate after procedure and she suffered disabling side‐effects. Clinics that give experimental...
Abstract Seven unrelated individuals (four pediatric, three adults) with the TUBB3 E410K syndrome, harboring identical de novo heterozygous c.1228 G>A mutations, underwent neuropsychological testing and neuroimaging. Despite absence of cortical malformations, they have intellectual social disabilities. To search for potential etiologies these deficits, we compared their brain's structural white matter organization to 22 controls using diffusion magnetic resonance imaging. Diffusion images...
The exact mechanisms underlying neuroinflammation and how they contribute to amyotrophic lateral sclerosis (ALS) pathogenesis remain unclear. One possibility is the secretion of neurotoxic factors, such as lipocalin-2 (LCN2), that lead neuronal death.LCN2 levels were measured in human postmortem tissue using Western blot, quantitative real time polymerase chain reaction, immunofluorescence, plasma by enzyme-linked immunosorbent assay. SH-SY5Y cells used test pro-inflammatory effects...
People living with ALS (plwALS) experience motor control loss, speech/swallowing difficulties, respiratory insufficiency, and early death. Advancing disease stage is typically associated a greater burden on the health care system, delays in diagnosis can result substantial resource utilization (HCRU).
Several clinical upper motor neuron burden scales (UMNSs) variably measure brain dysfunction in amyotrophic lateral sclerosis (ALS). Here, we compare relationship of two widely used UMNSs ALS (Penn and MGH UMNSs) with (a) neuroimaging markers (b) neurological impairment status using the gold-standard functional measure, revised Functional Rating Scale (ALSFRS-R). UMNS measures hyperreflexia alone, Penn hyperreflexia, spasticity, pseudobulbar affect. Twenty-eight participants underwent both...
We detected a novel imaging sign, which consists of specific pattern diffuse susceptibility effect, delineating the cortical-subcortical junction on high-resolution susceptibility-weighted images (SWIs). describe magnetic resonance findings in 10 patients with "susceptibility etching" and possible association their abnormal coagulation profile.A retrospective case series study search for cases that demonstrated effect at SWI sequences was performed. The patients' respective profiles...
SECTION 1An 82-year-old man with hypothyroidism presented difficulty walking.One year prior to presentation, he noticed that his legs occasionally "froze" when initiating walking.His gait progressively worsened over the year.He developed balance difficulty, tripping and falling twice without loss of consciousness.In 4 months started using a cane, rolling walker, then wheelchair.He reported occasional neck left leg cramps.He denied bowel or bladder symptoms.The patient was previously healthy,...