Apoptosis of Oligodendrocytes during Early Development Delays Myelination and Impairs Subsequent Responses to Demyelination.

During mammalian development, myelin-forming oligodendrocytes are generated and axons ensheathed according to a tightly regulated sequence of events. Excess premyelinating oligodendrocytes are eliminated by apoptosis and the timing of the onset of myelination in any specific CNS region is highly reproducible. Although the developing CNS recovers more effectively than the adult CNS from similar insults, it is unknown whether early loss of oligodendrocyte lineage cells leads to long-term functional deficits. To directly assess whether the loss of oligodendrocytes during early postnatal spinal cord development impacted oligodendrogenesis, myelination, and remyelination, transgenic mouse lines were generated in which a modified caspase-9 molecule allowed spatial and temporal control of the apoptotic pathway specifically in mature, myelin basic protein expressing oligodendrocytes (MBP-iCP9). Activating apoptosis in MBP(+) cells of the developing spinal cord during the first postnatal week inhibited myelination. This inhibition was transient, and the levels of myelination largely returned to normal after 2 weeks. Despite robust developmental plasticity, MBP-iCP9-induced oligodendrocyte apoptosis compromised the rate and extent of adult remyelination. Remyelination failure correlated with a truncated proliferative response of oligodendrocyte progenitor cells, suggesting that depleting the oligodendrocyte pool during critical developmental periods compromises the regenerative response to subsequent demyelinating lesions. SIGNIFICANCE STATEMENT: This manuscript demonstrates that early insults leading to oligodendrocyte apoptosis result in the impairment of recovery from demyelinating diseases in the adult. These studies begin to provide an initial understanding of the potential failure of recovery in insults, such as periventricular leukomalacia and multiple sclerosis.

Diagnosis and Management of Hypertension in Adolescents with Obesity.

Purpose of Review: Hypertension (HTN) and obesity are increasing in prevalence and severity in adolescents and have significant implications for long term morbidity and mortality. This review focuses on the diagnosis and management of HTN in adolescents with obesity with an emphasis on co-management of the two conditions. Recent Findings: Recent studies affirm the increasing prevalence of abnormal blood pressures and diagnoses of HTN associated with increased adiposity. Current guidelines recommend routine screening with proper technique for HTN in patients with obesity. Additionally, obesity and HTN related co-occurring medical conditions should be evaluated as there is frequently a bidirectional impact on risk and outcomes. Importantly, advances in adolescent obesity management have subsequently led to positive implications for the management of obesity-related comorbidities such as HTN. The co-management of obesity and HTN is an emerging strategy for treatment and prevention of additional morbidity and mortality as patients progress to adulthood. Summary: In adolescent patients with obesity, prompt recognition and appropriate diagnosis of HTN as well as related co-occurring conditions are necessary first steps in management. Co-management of obesity and HTN is likely to lead to improved outcomes. While lifestyle interventions serve as the foundation to this management, adjunctive and emerging therapies should be considered to adequately treat both conditions.

Cortical remyelination: a new target for repair therapies in multiple sclerosis.

OBJECTIVE: Generation and differentiation of new oligodendrocytes in demyelinated white matter is the best described repair process in the adult human brain. However, remyelinating capacity falters with age in patients with multiple sclerosis (MS). Because demyelination of cerebral cortex is extensive in brains from MS patients, we investigated the capacity of cortical lesions to remyelinate and directly compared the extent of remyelination in lesions that involve cerebral cortex and adjacent subcortical white matter. METHODS: Postmortem brain tissue from 22 patients with MS (age 27-77 years) and 6 subjects without brain disease were analyzed. Regions of cerebral cortex with reduced myelin were examined for remyelination, oligodendrocyte progenitor cells, reactive astrocytes, and molecules that inhibit remyelination. RESULTS: New oligodendrocytes that were actively forming myelin sheaths were identified in 30 of 42 remyelinated subpial cortical lesions, including lesions from 3 patients in their 70s. Oligodendrocyte progenitor cells were not decreased in demyelinated or remyelinated cortices when compared to adjacent normal-appearing cortex or controls. In demyelinated lesions involving cortex and adjacent white matter, the cortex showed greater remyelination, more actively remyelinating oligodendrocytes, and fewer reactive astrocytes. Astrocytes in the white matter, but not in cortical portions of these lesions, significantly upregulate CD44, hyaluronan, and versican, molecules that form complexes that inhibit oligodendrocyte maturation and remyelination. INTERPRETATION: Endogenous remyelination of the cerebral cortex occurs in individuals with MS regardless of disease duration or chronological age of the patient. Cortical remyelination should be considered as a primary outcome measure in future clinical trials testing remyelination therapies.

Weight Gain Patterns in Adolescent and Young Adult Women With the Etonogestrel Implant: Comparison by Weight Category.

PURPOSE: The purpose of this study was to determine if initiation and use of the etonogestrel implant was associated with differential weight gain in patients who were overweight or obese compared with normal-weight patients. METHODS: This is a cohort study of 1,024 patients between ages of 13 and 25 years seen in a Title X clinic who received the etonogestrel implant from 2007 to 2019 and had weight measurements at implant insertion and 6-18 months before (preinsertion) and after insertion (postinsertion). RESULTS: Patients, regardless of weight category (normal weight, overweight, and obese), increased weight in kilograms (kg) from preinsertion to insertion (1.16 ± 4.16 kg, 2.79 ± 5.35 kg, and 4.54 ± 7.71 kg, respectively) and from insertion to postinsertion (1.38 ± 4.37 kg, 2.94 ± 6.97 kg, and 3.66 ± 6.53, respectively). However, there was no increase in the amount gained comparing preinsertion to insertion with insertion to postinsertion. Patients who removed the implant (n = 84) for weight concerns did have increased weight change and a greater percent who gained ≥5% postinsertion as compared with those who removed the implant for other reasons or did not have the implant removed (65.5% vs. 34.2% vs. 39.2%, respectively, p = .03). CONCLUSIONS: Overweight and obese adolescents are at risk of weight gain over time, but placement of the implant did not accelerate the rate of gain from preinsertion to postinsertion. However, patients who removed the implant specifically because of weight gain did gain more weight after insertion compared with before. Clinicians should help patients evaluate the benefits and risks of highly effective contraceptive options as well as be aware of a subset of patients who do gain weight with use of the implant.

T1- and T2-based MRI measures of diffuse gray matter and white matter damage in patients with multiple sclerosis.

Magnetic resonance imaging (MRI) has emerged as a powerful noninvasive tool to assist in the diagnosis and monitoring of multiple sclerosis (MS). In addition, investigators have used MRI metrics as supportive outcome measures to explore drug efficacy in clinical trials. Conventional MRI surrogates provide information at the macroscopic level but lack sensitivity and specificity in identifying the full extent of underlying MS pathology. They also show relatively weak relationships to clinical status such as predictive strength for clinical change. Advanced MRI techniques involving quantitative measures of diffuse damage in normal appearing (NA) white matter (WM) and gray matter (GM) may help in resolving this apparent clinical MRI paradox. T2 hypointensity has been described in the GM of patients with MS and has been linked to physical disability, cognitive dysfunction, and brain atrophy. While this T2 hypointensity is thought to represent iron deposition, this awaits pathologic confirmation. Advanced MRI measures of iron deposition such as R2, R2*, R2' relaxometry, 3T imaging and other new approaches are beginning to be applied to studies of MS and should yield interesting information. Both T1 and T2 relaxometry have a role in detecting damage in NA brain tissue that escapes detection by conventional MRI lesion measures. For example, T2 mapping may allow an assessment of myelin content in NAWM. In this review, we will focus on MRI advances in the last 10 years pertaining to T1 and T2 measures of diffuse GM and WM damage.

Iron in chronic brain disorders: imaging and neurotherapeutic implications.

Iron is important for brain oxygen transport, electron transfer, neurotransmitter synthesis, and myelin production. Though iron deposition has been observed in the brain with normal aging, increased iron has also been shown in many chronic neurological disorders including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. In vitro studies have demonstrated that excessive iron can lead to free radical production, which can promote neurotoxicity. However, the link between observed iron deposition and pathological processes underlying various diseases of the brain is not well understood. It is not known whether excessive in vivo iron directly contributes to tissue damage or is solely an epiphenomenon. In this article, we focus on the imaging of brain iron and the underlying physiology and metabolism relating to iron deposition. We conclude with a discussion of the potential implications of iron-related toxicity to neurotherapeutic development.