Heterogeneity of factors associated with cognitive decline and cortical atrophy in early- versus late-onset Alzheimer's disease.

The objectives of this study were to investigate the variable factors associated with cognitive function and cortical atrophy and estimated variable importance of those factors in affecting cognitive function and cortical atrophy in patients with EOAD and LOAD. Patients with EOAD (n = 40), LOAD (n = 34), and healthy volunteers with normal cognition were included (n = 65). All of them performed 3T MRI, [18F]THK5351 PET (THK), [18F]flutemetamol PET (FLUTE), and detailed neuropsychological tests. To investigate factors associated with neuropsychological test results and cortical thickness in each group, we conducted multivariable linear regression models, including amyloid, tau, cerebral small vessel disease markers on MRI, and vascular risk factors. Then, we estimated variable importance in associating cognitive functions and cortical thickness, using relative importance analysis. In patients with EOAD, global THK retention was the most important contributor to the model variances for most neuropsychological tests, except for memory. However, in patients with LOAD, multiple contributors beyond tau were important in explaining variance of neuropsychological tests. In analyses with mean cortical thickness, global THK retention was the main contributor in patients with EOAD, while in LOAD patients, multiple factors contributed equally to mean cortical thickness. Therefore, EOAD and LOAD may have different pathomechanistic courses.

Diverging Relationships among Amyloid, Tau, and Brain Atrophy in Early-Onset and Late-Onset Alzheimer's Disease.

PURPOSE: Alzheimer's disease (AD) dementia may not be a single disease entity. Early-onset AD (EOAD) and late-onset AD (LOAD) have been united under the same eponym of AD until now, but disentangling the heterogeneity according to the age of sonset has been a major tenet in the field of AD research. MATERIALS AND METHODS: Ninety-nine patients with AD (EOAD, n=54; LOAD, n=45) and 66 cognitively normal controls completed both [18F]THK5351 and [18F]flutemetamol (FLUTE) positron emission tomography scans along with structural magnetic resonance imaging and detailed neuropsychological tests. RESULTS: EOAD patients had higher THK retention in the precuneus, parietal, and frontal lobe, while LOAD patients had higher THK retention in the medial temporal lobe. Intravoxel correlation analyses revealed that EOAD presented narrower territory of local FLUTE-THK correlation, while LOAD presented broader territory of correlation extending to overall parieto-occipito-temporal regions. EOAD patients had broader brain areas which showed significant negative correlations between cortical thickness and THK retention, whereas in LOAD, only limited brain areas showed significant correlation with THK retention. In EOAD, most of the cognitive test results were correlated with THK retention. However, a few cognitive test results were correlated with THK retention in LOAD. CONCLUSION: LOAD seemed to show gradual increase in tau and amyloid, and those two pathologies have association to each other. On the other hand, in EOAD, tau and amyloid may develop more abruptly and independently. These findings suggest LOAD and EOAD may have different courses of pathomechanism.

Pelizaeus-Merzbacher Disease with PLP1 Exon 1 Duplication, Previously Misdiagnosed as Cerebral Palsy: a Case Report.

Pelizaeus-Merzbacher disease (PMD) is a X-linked recessive disorder with dysmyelination in central nervous system caused by proteolipid protein 1 (PLP1) gene mutation. We report a case of PMD with PLP1 exon 1 duplication, previously misdiagnosed as cerebral palsy (CP). A 25-year-old male previously diagnosed as CP visited our clinic with progressive weakness and spasticity of bilateral lower limbs. Next generation sequencing revealed hemizygous duplication of exon 1 in PLP1. Additionally, multiplex ligation-dependent probe amplification assay of the patient's mother showed the same mutation, which could finally confirm the diagnosis as PMD. This patient received comprehensive rehabilitation program, and helped the patient to achieve functional improvement. Proper diagnosis and therapeutic plan will be needed for the patients with PMD, before diagnosing CP rashly.

Analysis of Pneumothorax in Noninvasive Ventilator Users With Duchenne Muscular Dystrophy.

BACKGROUND: With the advancement of cardiorespiratory interventions, the survival rate among patients with Duchenne muscular dystrophy (DMD) has increased. Subsequently, pneumothorax has become a significant problem in patients with prolonged ventilatory support. RESEARCH QUESTION: What are the frequency, recurrence rate, risk factors, and prognosis of pneumothorax in patients with DMD requiring noninvasive ventilation (NIV)? Also, are there known risk factors of pneumothorax on chest CT scans? STUDY DESIGN AND METHODS: This retrospective longitudinal cohort study included 176 patients treated between 2006 and 2019. We collected information regarding location, severity, treatment methods, recurrence frequency, abnormal findings on CT scanning, and date of death. We compared the pneumothorax and nonpneumothorax groups. We calculated the estimated survival probabilities from the age at NIV application according to pneumothorax occurrence. RESULTS: Sixteen of the 176 patients (9.0%) experienced pneumothorax (median age at diagnosis, 24.6 years; range, 20.7-33.7 years). Among the 16 patients, 15 demonstrated pneumothorax after NIV application (median time between diagnosis and initial NIV application, 5.6 years; range, 3 days-9.6 years). Sixteen patients experienced 31 episodes of pneumothoraces (range, one-five episodes); among them, seven episodes (22.6%) were asymptomatic. Known risk factors not clearly visible by radiography scans were found in chest CT scan in 11 patients (68.8%). Seven of 16 patients (43.8%) eventually sustained severe lung damage with pulmonary fibrosis. No significant between-group differences were found in body weight, BMI, and age at NIV application; however, the pneumothorax group showed a significantly higher mortality rate after NIV application. INTERPRETATION: On pneumothorax occurrence in patients with DMD, recurrences and severe lung damage are common; moreover, these patients show higher mortality rates than patients without pneumothorax. Chest CT scans should be performed to identify risk factors, and treatment should be initiated accordingly. In addition, physicians should consider chest CT scanning in the case of suspected pneumothorax, even if no radiographic abnormality is found.

Tracking Cognitive Decline in Amnestic Mild Cognitive Impairment and Early-Stage Alzheimer Dementia: Mini-Mental State Examination versus Neuropsychological Battery.

BACKGROUND/AIMS: Although the Mini-Mental State Examination (MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SOB), and neuropsychological batteries are widely used for evaluating cognitive function, it remains elusive which instrument best reflects the longitudinal disease progression in amnestic mild cognitive impairment (aMCI) and probable Alzheimer disease (AD). We investigated whether changes in these three instruments over time correlate with loss of cortical gray matter volume (cGMV). METHODS: We retrospectively investigated 204 patients (aMCI, n = 114; AD, n = 90) who had undergone MMSE, CDR-SOB, the dementia version of the Seoul Neuropsychological Screening Battery (SNSB-D), and 3-dimensional T1-weighted magnetic resonance images at least twice. We investigated the partial correlation between annual decline in test scores and percent change of cGMV. RESULTS: In aMCI patients, changes in the SNSB-D total score (r = 0.340, p < 0.001) and CDR-SOB (r = 0.222, p = 0.020), but not MMSE, showed a correlation with cGMV loss, with the SNSB-D total score showing the strongest correlation. In AD patients, decline in all three test scores correlated significantly with cGMV loss, with MMSE exhibiting the strongest correlation (r = 0.464, p < 0.001). CONCLUSION: In aMCI patients, neuropsychological battery, though time-consuming, was the most adequate tool in tracking disease progression. In AD patients, however, MMSE may be the most effective longitudinal monitoring tool when considering cost-effectiveness.

ACTH-producing neuroendocrine tumor of the pancreas: a case report and literature review.

Tumors that arise from the endocrine pancreas, or the islets of pancreas, are called pancreatic neuroendocrine tumors (NETs). Pancreatic NET have an incidence of <0.1 per one million persons, and can lead to secretion of ectopic adrenocorticotropic hormone (ACTH). Herein, we presented a case of patient with Cushing's syndrome as a result of ACTH-producing pancreatic NET, who underwent successful laparoscopic distal pancreatosplenectomy. A 40-year-old Korean female patient with ophthalmologic discomfort, osteoporosis, and unexplained hypokalemia was admitted to our hospital. Under the suspicion of ACTH producing pancreatic NET after the diagnostic workup, we decided to perform surgical resection. Laparoscopic distal pancreatosplenectomy was performed; and the pathological examination revealed a 1.5 cm-sized grade 2 neuroendocrine tumor of the pancreas, which was encapsulated within the pancreatic parenchyma. After the operation, the patient no longer displayed cushingoid features. ACTH-producing pancreatic NET is rare, but can be one of the causes of Cushing's syndrome. Surgical resection is a feasible option in treating ACTH-producing pancreatic NET.

Slit2 inactivates GSK3ß to signal neurite outgrowth inhibition.

Slit molecules comprise one of the four canonical families of axon guidance cues that steer the growth cone in the developing nervous system. Apart from their role in axon pathfinding, emerging lines of evidence suggest that a wide range of cellular processes are regulated by Slit, ranging from branch formation and fasciculation during neurite outgrowth to tumor progression and to angiogenesis. However, the molecular and cellular mechanisms downstream of Slit remain largely unknown, in part, because of a lack of a readily manipulatable system that produces easily identifiable traits in response to Slit. The present study demonstrates the feasibility of using the cell line CAD as an assay system to dissect the signaling pathways triggered by Slit. Here, we show that CAD cells express receptors for Slit (Robo1 and Robo2) and that CAD cells respond to nanomolar concentrations of Slit2 by markedly decelerating the rate of process extension. Using this system, we reveal that Slit2 inactivates GSK3ß and that inhibition of GSK3ß is required for Slit2 to inhibit process outgrowth. Furthermore, we show that Slit2 induces GSK3ß phosphorylation and inhibits neurite outgrowth in adult dorsal root ganglion neurons, validating Slit2 signaling in primary neurons. Given that CAD cells can be conveniently manipulated using standard molecular biological methods and that the process extension phenotype regulated by Slit2 can be readily traced and quantified, the use of a cell line CAD will facilitate the identification of downstream effectors and elucidation of signaling cascade triggered by Slit.

Engineering neuronal growth cones to promote axon regeneration over inhibitory molecules.

Neurons in the central nervous system (CNS) fail to regenerate axons after injuries due to the diminished intrinsic axon growth capacity of mature neurons and the hostile extrinsic environment composed of a milieu of inhibitory factors. Recent studies revealed that targeting a particular group of extracellular inhibitory factors is insufficient to trigger long-distance axon regeneration. Instead of antagonizing the growing list of impediments, tackling a common target that mediates axon growth inhibition offers an alternative strategy to promote axon regeneration. Neuronal growth cone, the machinery that derives axon extension, is the final converging target of most, if not all, growth impediments in the CNS. In this study, we aim to promote axon growth by directly targeting the growth cone. Here we report that pharmacological inhibition or genetic silencing of nonmuscle myosin II (NMII) markedly accelerates axon growth over permissive and nonpermissive substrates, including major CNS inhibitors such as chondroitin sulfate proteoglycans and myelin-associated inhibitors. We find that NMII inhibition leads to the reorganization of both actin and microtubules (MTs) in the growth cone, resulting in MT reorganization that allows rapid axon extension over inhibitory substrates. In addition to enhancing axon extension, we show that local blockade of NMII activity in axons is sufficient to trigger axons to grow across the permissive-inhibitory border. Together, our study proposes NMII and growth cone cytoskeletal components as effective targets for promoting axon regeneration.