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Biomedical subjects

Timothy M Miller

Publications and source records attributed to Timothy M Miller.

15 recordsLinked to original sources
PubMed2026

Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration.

Alzheimer's disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8+ T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8+ T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8+ T cell infiltration and glial activation. The remaining CD8+ T cells exhibit limited clonal expansion, consistent with impaired priming. We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation. Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8+ T cell accumulation in the brain and tau-mediated neurodegeneration.

Journal Article↗
PubMed2023

A DUAL MTOR/NAD+ ACTING GEROTHERAPY.

The geroscience hypothesis states that a therapy that prevents the underlying aging process should prevent multiple aging related diseases. The mTOR (mechanistic target of rapamycin)/insulin and NAD+ (nicotinamide adenine dinucleotide) pathways are two of the most validated aging pathways. Yet, it's largely unclear how they might talk to each other in aging. In genome-wide CRISPRa screening with a novel class of N-O-Methyl-propanamide-containing compounds we named BIOIO-1001, we identified lipid metabolism centering on SIRT3 as a point of intersection of the mTOR/insulin and NAD+ pathways. In vivo testing indicated that BIOIO-1001 reduced high fat, high sugar diet-induced metabolic derangements, inflammation, and fibrosis, each being characteristic of non-alcoholic steatohepatitis (NASH). An unbiased screen of patient datasets suggested a potential link between the anti-inflammatory and anti-fibrotic effects of BIOIO-1001 in NASH models to those in amyotrophic lateral sclerosis (ALS). Directed experiments subsequently determined that BIOIO-1001 was protective in both sporadic and familial ALS models. Both NASH and ALS have no treatments and suffer from a lack of convenient biomarkers to monitor therapeutic efficacy. A potential strength in considering BIOIO-1001 as a therapy is that the blood biomarker that it modulates, namely plasma triglycerides, can be conveniently used to screen patients for responders. More conceptually, to our knowledge BIOIO-1001 is a first therapy that fits the geroscience hypothesis by acting on multiple core aging pathways and that can alleviate multiple conditions after they have set in.

Preprint↗
PubMed2006

Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive paralysis arising from the premature death of motor neurons. An inherited form is caused by a dominant mutation in the ubiquitously expressed superoxide dismutase (SOD1). SOD1 mutant expression within motor neurons is a determinant of onset and early disease, and mutant accumulation within microglia accelerates disease progression. Muscle also is a likely primary source for toxicity, because retraction of motor axons from synaptic connections to muscle is among the earliest presymptomatic events. To test involvement of muscle in ALS, viral delivery of transcription-mediated siRNA is shown to suppress mutant SOD1 accumulation within muscle alone but to be insufficient to maintain grip strength, whereas delivery to both motor neurons and muscle is sufficient. Use of a deletable mutant gene to diminish mutant SOD1 from muscle did not affect onset or survival. Finally, follistatin expression encoded by adeno-associated virus chronically inhibited myostatin and produced sustained increases in muscle mass, myofiber number, and fiber diameter, but these increases did not affect survival. Thus, SOD1-mutant-mediated damage within muscles is not a significant contributor to non-cell-autonomous pathogenesis in ALS, and enhancing muscle mass and strength provides no benefit in slowing disease onset or progression.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Antisense oligonucleotide therapy for neurodegenerative disease.

Neurotoxicity from accumulation of misfolded/mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Since decreasing levels of proteins responsible for such accumulations is likely to ameliorate disease, a therapeutic strategy has been developed to downregulate almost any gene in the CNS. Modified antisense oligonucleotides, continuously infused intraventricularly, have been demonstrated to distribute widely throughout the CNS of rodents and primates, including the regions affected in the major neurodegenerative diseases. Using this route of administration, we found that antisense oligonucleotides to superoxide dismutase 1 (SOD1), one of the most abundant brain proteins, reduced both SOD1 protein and mRNA levels throughout the brain and spinal cord. Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis (ALS) caused by a mutation in SOD1. This suggests that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known.

Animals↗
PubMed2006

Progressive spinal axonal degeneration and slowness in ALS2-deficient mice.

OBJECTIVE: Homozygous mutation in the ALS2 gene and the resulting loss of the guanine exchange factor activity of the ALS2 protein is causative for autosomal recessive early-onset motor neuron disease that is thought to predominantly affect upper motor neurons. The goal of this study was to elucidate how the motor system is affected by the deletion of ALS2. METHODS: ALS2-deficient mice were generated by gene targeting. Motor function and upper and lower motor neuron pathology were examined in ALS2-deficient mice and in mutant superoxide dismutase 1 (SOD1) mice that develop ALS-like disease from expression of an ALS-linked mutation in SOD1. RESULTS: ALS2-deficient mice demonstrated progressive axonal degeneration in the lateral spinal cord that is also prominent in mutant SOD1 mice. Despite the vulnerability of these spinal axons, lower motor neurons in ALS2-deficient mice were preserved. Behavioral studies demonstrated slowed movement without muscle weakness in ALS2(-/-) mice, consistent with upper motor neuron defects that lead to spasticity in humans. INTERPRETATION: The combined evidence from mice and humans shows that deficiency in ALS2 causes an upper motor neuron disease that in humans closely resembles a severe form of hereditary spastic paralysis, and that is quite distinct from amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis↗
PubMed2006

The muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet): surveillance methodology.

BACKGROUND: This report focuses on the common protocol developed by the Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) for population-based surveillance of Duchenne and Becker muscular dystrophy (DBMD) among 4 states (Arizona, Colorado, Iowa, and New York). METHODS: The network sites have developed a case definition and surveillance protocol along with software applications for medical record abstraction, clinical review, and pooled data. Neuromuscular specialists at each site review the pooled data to determine if a case meets the case criteria. Sources of potential cases of DBMD include neuromuscular specialty clinics, service sites for children with special healthcare needs, and hospital discharge databases. Each site also adheres to a common information assurance protocol. RESULTS: A population-based surveillance system for DBMD was created and implemented in participating states. CONCLUSIONS: The development and implementation of the population-based system will allow for the collection of information that is intended to provide a greater understanding of DBMD prevalence and health outcomes.

Abstracting and Indexing↗
PubMed2005

Should the Babinski sign be part of the routine neurologic examination?

BACKGROUND: The Babinski sign is a well-known sign of upper motor neuron dysfunction that is widely considered an essential element of a complete neurologic examination. Little is known about reliability and validity of this sign. A less well-known sign of upper motor neuron dysfunction, decreased speed of foot tapping, also has not been carefully evaluated. Scientific evaluation of findings of the physical examination is crucial in directing busy clinicians. METHODS: Ten physicians (five neurologists and five non-specialists) examined each foot of 10 subjects, 8 of whom had known unilateral upper motor neuron weakness, 1 had bilateral leg weakness secondary to ALS, and 1 had no known neurologic deficits. Our main outcome measures were inter-rater reliability (kappa values) and accuracy (agreement with known upper motor neuron weakness). RESULTS: The reliability of the Babinski sign was fair (kappa 0.30) and was substantial for foot tapping (kappa 0.73). Agreement with known weakness was 56% for Babinski sign and 85% for foot tapping. Reliability and accuracy for both tests were similar for neurologists and non-specialists. CONCLUSIONS: The interobserver reliability and validity of the Babinski sign for identifying upper motor neuron weakness are limited. Slowness of foot tapping may be a more useful sign.

Adult↗
PubMed2005

Virus-delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis.

Mutations in superoxide dismutase cause a subset of familial amyotrophic lateral sclerosis and provoke progressive paralysis when expressed in mice. After retrograde transport to the spinal cord following injection into muscles, an adeno-associated virus carrying a gene that encodes a small interfering RNA was shown to target superoxide dismutase messenger RNA for degradation. The corresponding decrease in mutant superoxide dismutase in spinal motor neurons preserved grip strength. This finding provides proof of principle for the selective reduction of any neuronal protein and supports intramuscular injections of a small interfering RNA-encoding virus as a viable therapy for this type of familial amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Muscle cramps.

Muscle cramps are a common problem characterized by a sudden, painful, involuntary contraction of muscle. These true cramps, which originate from peripheral nerves, may be distinguished from other muscle pain or spasm. Medical history, physical examination, and a limited laboratory screen help to determine the various causes of muscle cramps. Despite the "benign" nature of cramps, many patients find the symptom very uncomfortable. Treatment options are guided both by experience and by a limited number of therapeutic trials. Quinine sulfate is an effective medication, but the side-effect profile is worrisome, and other membrane-stabilizing drugs are probably just as effective. Patients will benefit from further studies to better define the pathophysiology of muscle cramps and to find more effective medications with fewer side-effects.

Action Potentials↗
PubMed2004

Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria.

One cause of amyotrophic lateral sclerosis (ALS) is mutation in ubiquitously expressed copper/zinc superoxide dismutase (SOD1), but the mechanism of toxicity to motor neurons is unknown. Multiple disease-causing mutants, but not wild-type SOD1, are now demonstrated to be recruited to mitochondria, but only in affected tissues. This is independent of the copper chaperone for SOD1 and dismutase activity. Highly preferential association with spinal cord mitochondria is seen in human ALS for a mutant SOD1 that accumulates only to trace cytoplasmic levels. Despite variable proportions that are successfully imported, nearly constant amounts of SOD1 mutants and covalently damaged adducts of them accumulate as apparent import intermediates and/or are tightly aggregated or crosslinked onto integral membrane components on the cytoplasmic face of those mitochondria. These findings implicate damage from action of spinal cord-specific factors that recruit mutant SOD1 to spinal mitochondria as the basis for their selective toxicity in ALS.

Aging↗
PubMed2004

Proposed modification to data analysis for statistical motor unit number estimate.

Motor unit number estimation (MUNE) is an important electrophysiological technique for quantitative measurement of motor neuron loss. Although commonly used, there is no consensus concerning the optimal procedure for statistical MUNE, particularly regarding several operator-dependent variables. To assess the variables, we analyzed 500 sequential, submaximal compound muscle action potential (CMAP) responses at three or four stimulus intensities in 10 controls and 10 patients with amyotrophic lateral sclerosis (ALS). In both controls and ALS patients, we found that posttest filtering data based on 20% or 25% windows or 2, 2.5, or 3 SD excludes <5% of data. Windows of 10% or 15% excluded <5% of data in controls but not in ALS patients. Excluding data based on +/-2 SD, the coefficient of variation for final MUNE was 12% in controls and 6% in ALS patients. Group sizes of 30 or 50 and sample sizes of 300 to 500 sequential CMAP responses per run yielded the lowest coefficient of variation. We propose that statistical MUNE data should be analyzed based on excluding data >2 SD from the mean, because this is operator independent, includes the majority of data, effectively excludes clearly outlying data, such as fasciculations or movement artifact, and has a reasonable coefficient of variation.

Adult↗
PubMed2004

Unraveling the mechanisms involved in motor neuron degeneration in ALS.

Although Charcot described amyotrophic lateral sclerosis (ALS) more than 130 years ago, the mechanism underlying the characteristic selective degeneration and death of motor neurons in this common adult motor neuron disease has remained a mystery. There is no effective remedy for this progressive, fatal disorder. Modern genetics has now identified mutations in one gene [Cu/Zn superoxide dismutase (SOD1)] as a primary cause and implicated others [encoding neurofilaments, cytoplasmic dynein and its processivity factor dynactin, and vascular endothelial growth factor (VEGF)] as contributors to, or causes of, motor neuron diseases. These insights have enabled development of model systems to test hypotheses of disease mechanism and potential therapies. Along with errors in the handling of synaptic glutamate and the potential excitotoxic response this provokes, these model systems highlight the involvement of nonneuronal cells in disease progression and provide new therapeutic strategies.

Amyotrophic Lateral Sclerosis↗