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Objective: Persisting neurological symptoms after COVID-19 affect up to 10% of patients and can manifest in fatigue and cognitive complaints. Based on recent evidence, we evaluated whether cerebral hemodynamic changes contribute to post-COVID syndrome (PCS)., Methods: Using resting-state functional magnetic resonance imaging, we investigated brain perfusion and oxygen level estimates in 47 patients (44.4 ± 11.6 years; F:M = 38:9) and 47 individually matched healthy control participants. Group differences were calculated using two-sample t-tests. Multivariable linear regression was used for associations of each regional perfusion and oxygen level measure with cognition and sleepiness measures. Exploratory hazard ratios were calculated for each brain metric with clinical measures., Results: Patients presented with high levels of fatigue (79%) and daytime sleepiness (45%). We found widespread decreased brain oxygen levels, most evident in the white matter (false discovery rate adjusted-p-value (p- FDR ) = 0.038) and cortical grey matter (p- FDR  = 0.015). Brain perfusion did not differ between patients and healthy participants. However, delayed patient caudate nucleus perfusion was associated with better executive function (p- FDR  = 0.008). Delayed perfusion in the cortical grey matter and hippocampus were associated with a reduced risk of daytime sleepiness (hazard ratio (HR) = 0.07, p = 0.037 and HR = 0.06, p = 0.034). Decreased putamen oxygen levels were associated with a reduced risk of poor cognitive outcome (HR = 0.22, p = 0.019). Meanwhile, lower thalamic oxygen levels were associated with a higher risk of cognitive fatigue (HR = 6.29, p = 0.017)., Interpretation: Our findings of lower regional brain blood oxygen levels suggest increased cerebral metabolism in PCS, which potentially holds a compensatory function. These hemodynamic changes were related to symptom severity, possibly representing metabolic adaptations., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) are conditions whose closely related pathology suggests shared pathophysiological elements, but whose clinical courses are usually, but not always quite dissimilar. The former is largely a disease of adulthood, the latter of childhood. Optic neuritis, demyelinative transverse myelitis, and Devic's syndrome are neurological syndromes that may occur as manifestations of either MS or ADEM. Patients with Miller-Fisher syndrome and encephalomyelradiculoneuropathy usually have features suggesting ADEM in combination with acute demyelinative polyneuropathy. These various conditions and other forms of ADEM share an indistinct border with encephalitides, granulomatous, and vasculitic conditions. MS, ADEM, and the pertinent syndromic subtypes, their differential diagnosis, treatment, and prognosis are considered in this review. Acute cerebellar ataxia is a syndrome that is likely to be pathophysiologically distinct from ADEM, although its occurrence as a postinfectious illness suggests a distant kinship. It is also reviewed.

Congenital muscular dystrophies (CMDs) are autosomal recessive, heterogeneous disorders. The most frequent form in the Caucasian population is classic (occidental) CMD, characterized by exclusive muscle involvement, although abnormal brain white matter signals are occasionally observed on MRI. Recently, deficiency of merosin, the laminin isoform in skeletal muscle, has been identified in classic CMD patients. In skeletal muscle, merosin is a native ligand for dystroglycan linking the extracellular matrix and dystrophin. Thus, merosin deficiency could disrupt the attachment of muscle cell to the extracellular matrix and lead to muscle cell necrosis. Since merosin is also expressed in the nervous system and has biologic activities on neurite outgrowth and Schwann cell migration, deficiency of merosin could affect the development of the nervous system. We report here two patients with merosin-negative CMD presenting extensive brain abnormalities characterized by cortical anomaly, polymicrogyria, and abnormal white matter signals.

Recent publications concerning developmental changes in energy metabolism of brain have concentrated on three areas: 1) substrate priority for energy production; 2) balance between glycolytic and respiratory energy production; 3) variation in energy economy by cell type and stage of cellular differentiation; and 4) regional variation in energy reserves and energy demand. These studies have demonstrated a number of significant differences in the energy metabolism of developing brain. Some of these differences appear to derive from the low energy demands of developing brain, some appear to provide neuroprotective advantages (eg, adaptability in carbon sources, high glycogen stores), and some are of uncertain significance (eg, glycogen accumulation in radial glia).

Neurological abnormalities including agitation, confusion, disorientation, lethargy, and obtundation are early characteristic findings in patients with sepsis. The etiology of the changes in mental status that occur during severe infection is unknown. We investigated the effects of sepsis on intermediary metabolism and bioenergetics in the brain during normoxia and moderate hypoxia (8% inspired O2 concentration) in rats 36-42 hr following cecal ligation and perforation. The rats were anesthetized with halothane, and brains frozen using the funnel-freezing technique. Perchloric acid extracts of brains were analyzed with fluorometric enzymatic methods and 31P nuclear magnetic resonance spectroscopy. There was no impairment in bioenergetics or intermediary metabolism in septic brain, and sepsis did not compromise the ability of the brain to maintain high-energy phosphates during hypoxia. Hypoxia did cause the brain lactate-to-pyruvate ratio to increase equivalently in both septic and control rats from approximately 9:1 to 20:1 (P < 0.001). We conclude that the neurologic changes which are characteristic of sepsis are unlikely to be due to alterations in cellular energy stores or intermediately metabolism. In addition, there is no evidence that sepsis results in brain cellular hypoxia.

A new lethal familial syndrome of unknown etiology is described in two male siblings who died in the newborn period. Both had corneal edema and were hypotonic, requiring assisted ventilation at birth. Neuropathological findings included an immature appearance of neocortical neurons, with cortical architecture similar to that normally seen in an infant of 5 months gestational age. Axons and myelin were absent in the cerebral and cerebellar white matter, and also in descending white matter tracts of brainstem and spinal cord. Subacute inflammation was seen in the anterior horns of the spinal cord in both cases, although there was no evidence of inflammation elsewhere in the nervous system. Electron microscopy of endothelial cells from brain, spinal cord and a number of other tissues of the second sibling showed tubuloreticular inclusions (TRIs). There are no known previous reports of similar neuropathology. Future recognition of this condition will be important for genetic counselling.

Of brain dolichol compounds, dolichyl phosphate is most critical since it serves as the carrier of saccharide moieties to be utilized for N-linked protein glycosylation. The objectives of the current study were to determine (1) whether the proportion of dolichyl phosphate to dolichol in brain is relatively large and/or changes with development, and (2) whether the subcellular distribution of these isoprenoid compounds differs and/or changes with development. A recently described, improved technique for isolation and quantitation of dolichyl phosphate was employed. The data show that in the first 4 weeks of postnatal life in the rat dolichyl phosphate is, in fact, the predominant form of total dolichol compounds in brain. Subsequently, concentrations of dolichol exceeded those of dolichyl phosphate in adult brain, particularly with aging. Dolichyl phosphate was found to be localized primarily in microsomes; dolichol was found in only small amounts in microsomes but was enriched in the fraction that contained lysosomes. The observations indicate that during early brain development, an active time period for differentiating events, many of which are mediated by glycoproteins, dolichyl phosphate is present in high concentration at the subcellular site of N-linked glycoprotein synthesis, i.e., endoplasmic reticulum.

The capacity of brain to dephosphorylate glucose-6-phosphate has been established, but the magnitude and significance of this capacity in vivo are debated, particularly in regard to dephosphorylation of the glucose analog 2-deoxyglucose. We now report results of external measurement in the brains of conscious rats with simultaneous resolution and quantification of both 2-deoxyglucose and its phosphorylated product by nuclear magnetic resonance (NMR) techniques that used 2-[6-13]deoxyglucose together with proton-decoupled 13C surface-coil spectroscopy. As NMR techniques require large doses of 2-deoxyglucose, a dose comparison was first made using decay curves of total label after tracer doses of 2-[14C]deoxyglucose without versus with unlabeled deoxyglucose at 500 mg/kg (the NMR dose). Similar cerebral half-lives for the two doses were found, and no behavioral evidence for toxicity of the NMR dose was seen. In vivo NMR monitoring of conscious rats showed that the analog reached maximal cerebral concentration within 10 min of the intravenous bolus and decayed with a half-life of 29 +/- 7 min (n = 4; mean +/- SEM), whereas 2-deoxyglucose-6-phosphate reached peak concentration between 30 and 40 min and decayed with a half-life of 2.1 +/- 0.3 h, equivalent to a fractional loss of 0.8%/min. Thirty-one percent (+/- 5%) of the total analog pool (which showed a half-life of 1.4 h) consisted of 2-deoxyglucose at 45 min after the bolus. The results support an active but limited role for dephosphorylation by normal brain in glucose analog (and potentially glucose) metabolism in the unstimulated conscious rat and a wide concentration range for the metabolic operations involved.

The developmental changes of dolichol kinase activity and dolichyl phosphate levels have been studied in rat brain. Because both dolichol kinase activity and dolichyl phosphate were enriched in microsomes, detailed study of this subcellular fraction was carried out. Dolichol kinase specific activity in brain microsomes increased postnatally 3-fold to a maximum at ca. 30 days of age. This increase was observed whether exogenous dolichol was present or not and whether Zn2+ or Ca2+ was utilized as the cation for the enzyme. Zn2+ was the most effective cation in developing brain, as we have shown previously for adult brain (Sakakihara, Y. and Volpe, J.J., J. Biol. Chem., 260 (1985) 15413-15419). Although the Vmax for the enzyme increased by three-fold with development, the Km for dolichol and for CTP did not change, indicating that the developmental increase was not related to an alteration in catalytic efficiency of the enzyme. A striking and parallel increase in dolichyl phosphate levels in brain microsomes was defined with development. Levels were lowest in one-day-old animals and then increased ca. 13-fold to a maximum at 30 days of postnatal age. The parallel increase in dolichol kinase activity and dolichyl phosphate levels in microsomes of developing brain suggests that dolichol kinase is the principal determinant of cellular levels of dolichyl phosphate, the critical intermediate in the dolichol-linked pathway to glycoproteins.