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Current Neurology and Neuroscience... Jul 2023Apraxia of speech (AOS) is a motor speech disorder that has long been recognized to occur secondary to acute neurologic insults and, more recently, to neurodegenerative... (Review)
Review
PURPOSE OF REVIEW
Apraxia of speech (AOS) is a motor speech disorder that has long been recognized to occur secondary to acute neurologic insults and, more recently, to neurodegenerative diseases as a harbinger for progressive supranuclear palsy and corticobasal syndrome. This article reviews recent findings regarding the clinic phenotypes of AOS, neuroimaging correlates, and the underlying disease processes.
RECENT FINDINGS
Two clinical subtypes of AOS map onto two underlying 4-repeat tauopathies. New imaging techniques have recently been applied to the study of progressive AOS. There is no data on the impact of behavioral intervention, although studies of nonfluent/agrammatic primary progressive aphasia that include patients with AOS suggest some benefit in speech intelligibility and maintenance. While recent findings suggest subtypes of AOS exist that are linked to molecular pathology and have important implications for disease progression, further research is needed to assess outcome of behavioral and other types of intervention.
Topics: Humans; Speech; Apraxias; Supranuclear Palsy, Progressive; Neuroimaging; Neurodegenerative Diseases
PubMed: 37269450
DOI: 10.1007/s11910-023-01275-1 -
Indian Journal of Ophthalmology Jul 2023The optimal method of treatment for a child depends on the patient's age at the time of diagnosis, the onset and type of amblyopia, and the degree of compliance... (Review)
Review
The optimal method of treatment for a child depends on the patient's age at the time of diagnosis, the onset and type of amblyopia, and the degree of compliance attainable. In deprivation amblyopia, the cause of visual impairment (e.g., cataract, ptosis) needs to be treated first, and then the disorder can be treated such as other types of amblyopia. Anisometropic amblyopia needs glasses first. In strabismic amblyopia, conventionally amblyopia should be treated first, and then strabismus corrected. Correction of strabismus will have little if any effect on the amblyopia, although the timing of surgery is controversial. Best outcomes are achieved if amblyopia is treated before the age of 7 years. The earlier the treatment, the more efficacious it is. In selected cases of bilateral amblyopia, the more defective eye must be given a competitive advantage over the comparatively good eye. Glasses alone can work when a refractive component is present, but occlusion might make the glasses work faster. The gold standard therapy for amblyopia remains occlusion of the better eye although penalization is also evidenced to achieve equal results. Pharmacotherapy has been shown to achieve suboptimal outcomes. Newer monocular and binocular therapies based on neural tasks and games are adjuncts to patching and can also be used in adults.
Topics: Child; Adult; Humans; Amblyopia; Visual Acuity; Sensory Deprivation; Strabismus; Refraction, Ocular; Treatment Outcome
PubMed: 37417105
DOI: 10.4103/IJO.IJO_338_23 -
Annual Review of Physiology Feb 2024Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron.... (Review)
Review
Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron. Moreover, mitochondria contribute to cellular health by the regulation of autophagy, (oxidative) stress responses, and apoptosis. Mitochondrial abundance is particularly high in cortical segments, including proximal and distal convoluted tubules. Dysfunction of the mitochondria has been described for tubulopathies such as Fanconi, Gitelman, and Bartter-like syndromes and renal tubular acidosis. In addition, mitochondrial cytopathies often affect renal (tubular) tissues, such as in Kearns-Sayre and Leigh syndromes. Nevertheless, the mechanisms by which mitochondrial dysfunction results in renal tubular diseases are only scarcely being explored. This review provides an overview of mitochondrial dysfunction in the development and progression of kidney tubulopathies. Furthermore, it emphasizes the need for further mechanistic investigations to identify links between mitochondrial function and renal electrolyte reabsorption.
Topics: Humans; Kidney Tubules; Bartter Syndrome; Kearns-Sayre Syndrome; Kidney Diseases; Mitochondria
PubMed: 38012047
DOI: 10.1146/annurev-physiol-042222-025000 -
Proceedings of the National Academy of... Oct 2023Despite much effort, antibody therapies for Alzheimer's disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include the...
Despite much effort, antibody therapies for Alzheimer's disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include the difficulty of achieving specific affinity to critical targets, poor expression, and antibody aggregation caused by buried charges and unstructured loops. To overcome these challenges, we grafted previously determined sequences of fibril-capping amyloid inhibitors onto a camel heavy chain antibody scaffold. These sequences were designed to cap fibrils of tau, known to form the neurofibrillary tangles of AD, thereby preventing fibril elongation. The nanobodies grafted with capping inhibitors blocked tau aggregation in biosensor cells seeded with postmortem brain extracts from AD and progressive supranuclear palsy (PSP) patients. The tau capping nanobody inhibitors also blocked seeding by recombinant tau oligomers. Another challenge to the design of effective antibodies is their poor blood-brain barrier (BBB) penetration. In this study, we also designed a bispecific nanobody composed of a nanobody that targets a receptor on the BBB and a tau capping nanobody inhibitor, conjoined by a flexible linker. We provide evidence that the bispecific nanobody improved BBB penetration over the tau capping inhibitor alone after intravenous administration in mice. Our results suggest that the design of synthetic antibodies that target sequences that drive protein aggregation may be a promising approach to inhibit the prion-like seeding of tau and other proteins involved in AD and related proteinopathies.
Topics: Humans; Animals; Mice; Alzheimer Disease; tau Proteins; Single-Domain Antibodies; Neurofibrillary Tangles; Supranuclear Palsy, Progressive; Antibodies; Brain
PubMed: 37801475
DOI: 10.1073/pnas.2300258120 -
Cell May 2024Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we...
Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer's Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.
Topics: Humans; Induced Pluripotent Stem Cells; tau Proteins; Tauopathies; Neurons; Animals; Mice; Alzheimer Disease; Brain; Supranuclear Palsy, Progressive; Cell Differentiation; Mutation; Autophagy
PubMed: 38582079
DOI: 10.1016/j.cell.2024.03.015 -
Current Opinion in Neurology Jun 2024Anti-IgLON5 disease is characterized by a distinctive sleep disorder, associated with a heterogeneous spectrum of neurological symptoms. Initial autopsies showed a novel... (Review)
Review
PURPOSE OF REVIEW
Anti-IgLON5 disease is characterized by a distinctive sleep disorder, associated with a heterogeneous spectrum of neurological symptoms. Initial autopsies showed a novel neuronal tauopathy predominantly located in the tegmentum of the brainstem. Recently, new diagnostic red flags, biomarkers predictors of response to immunotherapy, and novel insights into the autoimmune pathogenesis of the disease have been reported.
RECENT FINDINGS
Patients with diagnosis of neurodegenerative dementia, progressive supranuclear palsy (PSP) or with motor-neuron disease (MND)-like syndrome have been reported to have IgLON5 antibodies, which are the hallmark of anti-IgLON5 disease. Second, low levels of neurofilament light chain in serum and cerebrospinal fluid of patients at disease onset could be a predictor of immunotherapy response. Recent neuropathological studies indicate that the neuronal tau deposits occur late in the course of the disease. Moreover, IgLON5 antibodies induce cytoskeletal changes in cultured hippocampal neurons suggesting that the tauopathy could be secondary of the IgLON5 antibody effects.
SUMMARY
Anti-IgLON5 disease can mimic and should be considered in atypical presentations of MND, neurodegenerative dementia and PSP. Neurofilament light chain levels seem promising biomarker for disease prognosis. Finally, the neuropathological and in vitro experimental studies strengthen the autoimmune hypothesis of the disease.
Topics: Animals; Humans; Autoantibodies; Biomarkers; Cell Adhesion Molecules, Neuronal; Neurofilament Proteins; Supranuclear Palsy, Progressive; Motor Neuron Disease; Neurodegenerative Diseases
PubMed: 38563128
DOI: 10.1097/WCO.0000000000001271 -
Neurotherapeutics : the Journal of the... Mar 2024The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction and accumulation of insoluble tau protein. Among them,... (Review)
Review
The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction and accumulation of insoluble tau protein. Among them, Alzheimer's disease, frontotemporal dementia, and progressive supranuclear palsy collectively impact millions of patients and their families worldwide. Despite years of drug development using a variety of mechanisms of action, no therapeutic directed against tau has been approved for clinical use. This raises important questions about our current model of tau pathology and invites thoughtful consideration of our approach to nonclinical models and clinical trial design. In this article, we review what is known about the biology and genetics of tau, placing it in the context of current and failed clinical trials. We highlight potential reasons for the lack of success to date and offer suggestions for new pathways in therapeutic development. Overall, our viewpoint to the future is optimistic for this important group of neurodegenerative diseases.
Topics: Humans; tau Proteins; Alzheimer Disease; Tauopathies; Supranuclear Palsy, Progressive; Neurodegenerative Diseases
PubMed: 38278659
DOI: 10.1016/j.neurot.2024.e00321 -
Medicine Oct 2023Adolescent scoliosis is one of the most common surgical disorders of the pediatric spine. With timely detection and early treatment, most scoliotic children can avoid... (Review)
Review
Adolescent scoliosis is one of the most common surgical disorders of the pediatric spine. With timely detection and early treatment, most scoliotic children can avoid major and expensive surgery. Vision problems are also frequently found at an early age and can take a toll on individuals quality of life. However, scoliosis, a severe health hazard to adolescents, is often accompanied by vision problems clinically, including myopia, astigmatism, strabismus, amblyopia, horizontal paralysis, and blindness. And people with genetic defects have a higher probability of suffering both spinal problems and vision problems than those with nongenetic defects. However, many individuals viewed scoliosis and vision problems as 2 irrelevant diseases. This review searched PubMed, China National Knowledge Infrastructure, and Web of Science for studies on adolescent, scoliosis, eye diseases, myopia, strabismus, spinal disorders, and vision problems for almost 3 decades, and thus confirmed the potential relationship between adolescent scoliosis and vision problems.
Topics: Adolescent; Humans; Child; Scoliosis; Quality of Life; Amblyopia; Strabismus; Myopia
PubMed: 37861544
DOI: 10.1097/MD.0000000000035178