Amnestic and non-amnestic symptoms of dementia: An international study of Alzheimer's disease in people with Down's syndrome.

The presence of age-related neuropathology characteristic of Alzheimer's disease (AD) in people with Down syndrome (DS) is well-established. However, the early symptoms of dementia may be atypical and appear related to dysfunction of prefrontal circuitry. OBJECTIVE: To characterize the initial informant reported age-related neuropsychiatric symptoms of dementia in people with DS, and their relationship to AD and frontal lobe function. METHODS: Non-amnestic informant reported symptoms (disinhibition, apathy, and executive dysfunction) and amnestic symptoms from the CAMDEX-DS informant interview were analyzed in a cross-sectional cohort of 162 participants with DS over 30 years of age, divided into three groups: stable cognition, prodromal dementia, and AD. To investigate age-related symptoms prior to evidence of prodromal dementia we stratified the stable cognition group by age. RESULTS: Amnestic and non-amnestic symptoms were present before evidence of informant-reported cognitive decline. In those who received the diagnosis of AD, symptoms tended to be more marked. Memory impairments were more marked in the prodromal dementia than the stable cognition group (OR = 35.07; P < .001), as was executive dysfunction (OR = 7.16; P < .001). Disinhibition was greater in the AD than in the prodromal dementia group (OR = 3.54; P = .04). Apathy was more pronounced in the AD than in the stable cognition group (OR = 34.18; P < .001). CONCLUSION: Premorbid amnestic and non-amnestic symptoms as reported by informants increase with the progression to AD. For the formal diagnosis of AD in DS this progression of symptoms needs to be taken into account. An understanding of the unique clinical presentation of DS in AD should inform treatment options.

Reduced expression of DNA repair genes and chemosensitivity in 1p19q codeleted lower-grade gliomas.

BACKGROUND: Lower-grade gliomas (LGGs, defined as WHO grades II and III) with 1p19q codeletion have increased chemosensitivity when compared to LGGs without 1p19q codeletion, but the mechanism is currently unknown. METHODS: RNAseq data from 515 LGG patients in the Cancer Genome Atlas (TCGA) were analyzed to compare the effect of expression of the 9 DNA repair genes located on chromosome arms 1p and 19q on progression free survival (PFS) and overall survival (OS) between patients who received chemotherapy and those who did not. Chemosensitivity of cells with DNA repair genes knocked down was tested using MTS cell proliferation assay in HS683 cell line and U251 cell line. RESULTS: The expression of 9 DNA repair genes on 1p and 19q was significantly lower in 1p19q-codeleted tumors (n = 175) than in tumors without the codeletion (n = 337) (p < 0.001). In LGG patients who received chemotherapy, lower expression of LIG1, POLD1, PNKP, RAD54L and MUTYH was associated with longer PFS and OS. This difference between chemotherapy and non-chemotherapy groups in the association of gene expression with survival was not observed in non-DNA repair genes located on chromosome arms 1p and 19q. MTS assays showed that knockdown of DNA repair genes LIG1, POLD1, PNKP, RAD54L and MUTYH significantly inhibited recovery in response to temozolomide when compared with control group (p < 0.001). CONCLUSIONS: Our results suggest that reduced expression of DNA repair genes on chromosome arms 1p and 19q may account for the increased chemosensitivity of LGGs with 1p19q codeletion.

Early neurologic deterioration with symptomatic isolated internal carotid artery occlusion: a cohort study, systematic review, and meta-analysis.

Background: Acute endovascular revascularization for isolated internal carotid occlusion without tandem intracranial occlusion has been proposed to prevent early neurologic deterioration (END) and improve outcome, but has not been shown to be more effective than medical therapy. We aimed to evaluate prognosis with initial medical therapy alone, and also performed a systematic review to put these results in a broader context. Methods: We performed a retrospective cohort study of patients admitted over a 2-year period with acute stroke/TIA due to isolated internal carotid artery occlusion. Subjects with tandem intracranial occlusion or ASPECTS≤5 were excluded. The primary outcome was END within 48 hours (NIHSS increase ≥4 persisting for ≥24 hours). Secondary outcomes included discharge NIHSS and disposition. We also performed a systematic review and meta-analysis of published studies along with the data from our cohort. Results: Twenty-three patients met our inclusion criteria. Median age was 69 years, initial ASPECTS 10, and NIHSS score 3. END attributed to recurrent ischemia occurred in 5/23 patients (22%, 95%CI: 7-44%). At discharge, 78% had a favorable outcome with a median NIHSS of 2 (IQR 1-3). END appeared more frequent in those with higher baseline NIHSS. In our systematic review, 7 prior studies met our inclusion criteria. END occurred in 17% (95%CI:12-23%) of patients, 18% with medical therapy versus 13% with endovascular therapy, with substantial heterogeneity among studies. Conclusions: In patients with acute stroke or TIA due to isolated internal carotid occlusion, END is relatively common (occurring in about 1 out of 6 patients). Further research is needed to evaluate the roles of maximal medical management or acute endovascular thrombectomy in these patients.

Association of Autonomic Storming with Urinary Catheter Removal in NMDA Receptor Encephalitis: A Case Report.

We present a case of a 47-year-old female who presented with altered mental status and was found to have severe anti-NMDA receptor encephalitis. Her intensive care unit course was complicated by paroxysmal sympathetic storming. She also had urinary retention for which a catheter was placed early in her admission, but attempts at removal were associated with worsening storming. Her average Clinical Features Scale score was 5.9 when the catheter was not in place compared to 3.6 with the catheter in place. This is the first case report to our knowledge demonstrating an association between urinary catheter removal and autonomic storming in anti-NMDA receptor encephalitis.

Surgical Management of Idiopathic Thoracic Spinal Cord Herniation.

BACKGROUND: Idiopathic spinal cord herniation is a rare condition that involves spinal cord herniation through a defect in the ventral dura. CASE DESCRIPTION: We present a case of a 61-year-old woman who initially presented in 2016 with an approximately 1-year history of burning right lower extremity pain and gait instability. Her neurologic examination was consistent with thoracic Brown-Sequard syndrome, and spinal magnetic resonance imaging showed a focal defect in the ventral dura at the superior aspect of T4 with the left aspect of the cord herniating into the defect. In 2018, she underwent a T3-T4 laminectomy with T3 pedicle take down and medial facetectomy, with reduction of the herniated cord. CONCLUSIONS: Idiopathic spinal cord herniation is an uncommon spinal cord disorder with a paucity of data reported. Our case report of a classic case of idiopathic spinal cord herniation presenting as Brown-Sequard syndrome and managed surgically will contribute to the data in this field.

Neuroimaging and other modalities to assess Alzheimer's disease in Down syndrome.

People with Down syndrome (DS) develop Alzheimer's disease (AD) at higher rates and a younger age of onset compared to the general population. As the average lifespan of people with DS is increasing, AD is becoming an important health concern in this group. Neuroimaging is becoming an increasingly useful tool in understanding the pathogenesis of dementia development in relation to clinical symptoms. Furthermore, neuroimaging has the potential to play a role in AD diagnosis and monitoring of therapeutics. This review describes major recent findings from in vivo neuroimaging studies analysing DS and AD via ligand-based positron emission tomography (PET), [18F] fluorodeoxyglucose (FDG)-PET, structural magnetic resonance imaging (sMRI), and diffusion tensor imaging (DTI). Electroencephalography (EEG) and retinal imaging are also discussed as emerging modalities. The review is organized by neuroimaging method and assesses the relationship between cognitive decline and neuroimaging changes. We find that amyloid accumulation seen on PET occurs prior to dementia onset, possibly as a precursor to the atrophy and white matter changes seen in MRI studies. Future PET studies relating tau distribution to clinical symptoms will provide further insight into the role this protein plays in dementia development. Brain activity changes demonstrated by EEG and metabolic changes seen via FDG-PET may also follow predictable patterns that can help track dementia progression. Finally, newer approaches such as retinal imaging will hopefully overcome some of the limitations of neuroimaging and allow for detection of dementia at an earlier stage.

Comparison of Adjuvant Radiation Therapy Alone and Chemotherapy Alone in Surgically Resected Low-Grade Gliomas: Survival Analyses of 2253 Cases from the National Cancer Data Base.

BACKGROUND: It is becoming increasingly common to incorporate chemotherapy (CT) with radiotherapy (RT) in the treatment of low-grade gliomas (LGGs) after surgical resection. However, there is a lack of literature comparing survival of patients who underwent RT or CT alone. METHODS: The U.S. National Cancer Data Base was used to identify patients with histologically confirmed, World Health Organization grade 2 gliomas who received either RT alone or CT alone after surgery from 2004 to 2013. Overall survival (OS) was evaluated by Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and propensity-score-matched analysis. RESULTS: In total, 2253 patients with World Health Organization grade 2 gliomas were included, of whom 1466 (65.1%) received RT alone and 787 (34.9%) CT alone. The median OS was 98.9 months for the RT alone group and 125.8 months for the CT alone group. On multivariable analysis, CT alone was associated with a significant OS benefit compared with RT alone (hazard ratio [HR], 0.405; 95% confidence interval, 0.277-0.592; P < 0.001). On subgroup analyses, the survival advantage of CT alone over RT alone persisted across all age groups, and for the subtotal resection and biopsy groups, but not in the gross total resection group. In propensity-score-matched analysis, CT alone still showed significantly improved OS compared with RT alone (HR, 0.612; 95% confidence interval, 0.506-0.741; P < 0.001). CONCLUSIONS: Our results suggest that CT alone was independently associated with longer OS compared with RT alone in patients with LGGs who underwent surgery.

Prognostic Factors in Clival Chordomas: An Integrated Analysis of 347 Patients.

OBJECTIVE: To investigate prognostic factors of clival chordoma using the largest patient set to date. METHODS: Appropriate studies were identified per search criteria, data satisfying criteria were extracted, and survival analysis was performed to investigate prognostic factors of clival chordoma. RESULTS: A total of 347 patients from the literature cohort met our inclusion criteria. Of 346 cases in which extent of resection was reported, gross total resection (GTR), subtotal resection, and biopsy were achieved in 118 (34.1%), 205 (59.2%), and 21 (6.1%) cases, respectively. Two (0.6%) subjects did not undergo surgery. Of 185 cases in which surgical approach was reported, 56 (30.3%) underwent an endoscopic transoral approach, 17 (9.2%) microscopic transsphenoidal, 45 (24.3%) endoscopic or microscopic, 45 (24.3%) craniotomy, and 22 (11.9%) other approaches. There was no significant difference in GTR rates of different surgical approaches (P = 0.101). Median follow-up was 46.6 months. The 5- and 10-year rates for progression-free survival (PFS) were 59.2% and 47.9%, respectively. The 5- and 10-year rates for overall survival (OS) were 77.3% and 63.9%, respectively. On multivariate analysis for both PFS and OS, GTR demonstrated significantly improved outcomes when compared with subtotal resection (hazard ratio 0.45, 95% confidence interval 0.22-0.90, P = 0.025 for PFS; hazard ratio 0.20, confidence interval 0.06-0.65, P = 0.008 for OS). CONCLUSIONS: GTR rates were comparable in different surgical approaches. GTR was a significant predictor of longer PFS and OS in clival chordoma.

Tumour necrosis factor gene complex polymorphisms in chronic obstructive pulmonary disease.

We aimed to examine the role of tumour necrosis factor gene complex polymorphisms in subjects with chronic obstructive pulmonary disease (COPD). We hypothesized that individuals possessing polymorphic variants associated with higher tumour necrosis factor (TNF) secretion would be more susceptible to and/or have more severe disease. Patients with COPD and population controls underwent detailed clinical phenotyping. Genotyping for the tumour necrosis factor-308 and the lymphotoxin alpha NcoI (LTalpha polymorphisms was carried out by 'blinded' laboratory staff. Three hundred and sixty one individuals (220 cases and 141 controls) were recruited. We showed an association between the LTalphaNcol polymorphism and forced vital capacity (FVC) in a population of older adults with and without COPD. The LTalphaNcol*2 allele was associated with poorer lung function, under a codominant model, with a fall in FVC (expressed as a percentage of its predicted value) of 3.7% for each copy of the LTalphaNcol*2 allele possessed (for FVC, regression coefficient (95% CI)=-3.73(-7.01 to -0.44), P=0.026; for FEV(1) regression coefficient=-3.56(-7.80 to 0.70), P=0.101. However, there was no difference in genotype distribution between the case and control populations. This study adds weight to the suggestion that the TNF gene complex is involved in physiological alterations (FVC) that may affect the development and severity of COPD. The absence of a significant association between the TNF gene-complex polymorphisms in this study does not rule out a modest effect of these polymorphisms on the risk of COPD, as much larger studies are needed to detect modest gene effects on binary disease endpoints.

Sputum and bronchial submucosal IL-13 expression in asthma and eosinophilic bronchitis.

BACKGROUND: Nonasthmatic eosinophilic bronchitis is a condition characterized by the presence of eosinophilic airway inflammation in the absence of airflow obstruction or airway hyperresponsiveness. In asthma, the T H 2-type cytokine IL-13 has been implicated in the development of airway inflammation and hyperresponsiveness. Whether the expression of IL-13 is different between these 2 conditions is unknown. OBJECTIVE: We sought to investigate whether IL-13 expression is increased in asthma compared with eosinophilic bronchitis. METHODS: Sputum samples from subjects with mild asthma (n = 30) and eosinophilic bronchitis (n = 15) and normal controls (n = 16) were dialyzed, and IL-13 concentration was measured by ELISA. In a subgroup of these patients, IL-13 protein expression in bronchial biopsies was assessed by immunohistochemistry. RESULTS: The concentration of sputum IL-13 was higher in patients with mild asthma than in normal controls ( P = .03) and in patients with eosinophilic bronchitis ( P = .03). The median (interquartile range) number of IL-13 + cells/mm 2 submucosa was significantly higher in asthma 4 (8) than eosinophilic bronchitis 1.7 (1.9) and normal controls 0.5 (1.1; P = .004). Eighty-three percent of the cells expressing IL-13 in the submucosa were eosinophils, and 8% were mast cells. The median (interquartile range) proportion of eosinophils that expressed IL-13 was higher in the subjects with asthma, 16 (10)%, than those with eosinophilic bronchitis, 7 (3)% ( P = .02). CONCLUSION: The increased expression of IL-13 in asthma compared with eosinophilic bronchitis supports the concept that IL-13 may play a critical role in the pathophysiology of asthma.