Decline In Neurocognitive Function Research Articles

Klotho Expression in Aging and Disease

Klotho is a regulatory anti‐aging protein that is significantly expressed in the choroid plexus, plays an important role in regulating the immune response in the CNS, and diminishes with age. It is known that a decline of klotho expression has been linked to significant neuroinflammation, oxidative damage in the neural parenchyma, and decline in neurocognitive functions. As the choroid plexus is a known reservoir for latent Human Immunodeficiency Virus (HIV) infection, the relationship between HIV and klotho expression could be a cause of the neurocognitive dysfunction that accompanies HIV infections. The objective of this project was to observe levels of klotho expression in the choroid plexus in a Simian Immunodeficiency Virus (SIV) model of HIV infection, as well as to determine a pattern of age‐related decline in klotho expression. To carry out the study, Choroid plexus samples of Rhesus macaques of various ages and SIV‐infection status were studied. The tissues were stained using immunohistochemistry for polyclonal klotho, structural proteins (vimentin), and nuclei (DAPI), and imaged at varying magnifications of 4x, 10x, and 40x. The images obtained were then analyzed using the fluorescent imaging software Fiji. The epithelial cells of the choroid plexus were measured for their fluorescence intensity to measure their relative klotho expression levels. Although klotho expression was varied in the uninfected Rhesus macaques, there was an overall decreasing trend with the advancement of age. In SIV‐infected Rhesus macaques, the choroid plexus had significantly less klotho expression than the uninfected control group regardless of age (p=0.01). Analysis of the uninfected data shows that there was a decreasing pattern of klotho expression in Rhesus macaques. The variability of klotho levels in the uninfected individuals can be attributed to genetic variations between individuals. However, SIV infection significantly reduced klotho expression in the choroid plexus in comparison to uninfected individuals. This decrease in klotho expression was regardless of age. The exact mechanism in which SIV diminishes klotho expression is unknown and additional studies are warranted to examine this phenomenon.

Neurocognitive function and survival in children with average-risk medulloblastoma treated with hyperfractionated radiation therapy alone: Long-term mature outcomes of a prospective study.

The purpose of this study was to report long-term neurocognitive and clinical outcomes in children treated for average-risk medulloblastoma with hyperfractionated radiation therapy (HFRT) alone. Between 2006 and 2010, 20 children with rigorously staged average-risk medulloblastoma were treated on a prospective study with HFRT without upfront adjuvant systemic chemotherapy after written informed consent. HFRT was delivered as twice-daily fractions (1 Gy/fraction, 6-8 hours apart, 5 days/week) to craniospinal axis (36 Gy/36 fractions) plus conformal tumor-bed boost (32 Gy/32 fractions). Neurocognitive function was assessed at baseline and periodically on follow-up using age-appropriate intelligence quotient (IQ) scales. Median age was 8 years (range 5-14 years) with 70% being males. Mean and standard deviation (SD) scores at baseline were 90.5 (SD = 17.08), 88 (SD = 16.82) and 88 (SD = 17.24) for Verbal Quotient (VQ), Performance Quotient (PQ), and Full-Scale IQ (FSIQ) respectively. Mean scores remained stable in the short-to-medium term but declined gradually beyond 5 years with borderline statistical significance for VQ (P = .042), but nonsignificant decline in PQ (P = .259) and FSIQ (P = .108). Average rate of neurocognitive decline was <1 IQ point per year over a 10-year period. Regression analysis stratified by age, gender, and baseline FSIQ failed to demonstrate any significant impact of the tested covariates on longitudinal neurocognitive function. At a median follow-up of 145 months, 10-year Kaplan-Meier estimates of progression-free survival and overall survival were 63.2% and 74.1% respectively. HFRT alone without upfront adjuvant chemotherapy in children with average-risk medulloblastoma is associated with modest decline in neurocognitive functioning with acceptable long-term survival outcomes and may be most appropriate for resource-constrained settings.

Extracellular vesicles released after cranial radiation: An insight into an early mechanism of brain injury

Cranial radiation is important for treating both primary brain tumors and brain metastases. A potential delayed side effect of cranial radiation is neurocognitive function decline. Early detection of CNS injury might prevent further neuronal damage. Extracellular vesicles (EVs) have emerged as a potential diagnostic tool because of their unique membranous characteristics and cargos. We investigated whether EVs can be an early indicator of CNS injury by giving C57BJ/6 mice 10 Gy cranial IR. EVs were isolated from sera to quantify: 1) number of EVs using nanoparticle tracking analysis (NTA); 2) Glial fibrillary acidic protein (GFAP), an astrocyte marker; and 3) protein-bound 4-hydroxy-2-nonenal (HNE) adducts, an oxidative damage marker. Brain tissues were prepared for immunohistochemistry staining and protein immunoblotting. The results demonstrate: 1) increased GFAP levels (p < 0.05) in EVs, but not brain tissue, in the IR group; and 2) increased HNE-bound protein adduction levels (p < 0.05). The results support using EVs as an early indicator of cancer therapy-induced neuronal injury.

Genetic modulation of longitudinal change in neurocognitive function among adult glioma patients.

Impaired neurocognitive function (NCF) is extremely common in patients with higher grade primary brain tumor. We previously reported evidence of genetic variants associated with NCF in glioma patients prior to treatment. However, little is known about the effect of genetic variants on NCFdecline after adjuvant therapy. Patients (N = 102) completed longitudinal NCF assessments that included measures of verbal memory, processing speed, and executive function. Testing was conducted in the postoperative period with an average follow up interval of 1.3years. We examined polymorphisms in 580 genes related to five pathways (inflammation, DNA repair, metabolism, cognitive, and telomerase). Five polymorphisms were associated with longitudinal changes in processing speed and 14 polymorphisms with executive function. Change in processing speed was strongly associated with MCPH1 rs17631450 (P = 2.2 × 10-7) and CCDC26 rs7005206 (P = 9.3 × 10-7) in the telomerase pathway; while change in executive function was more strongly associated with FANCF rs1514084 (P = 2.9 × 10-6) in the DNA repair pathway and DAOA rs12428572 (P = 2.4 × 10-5) in the cognitive pathway. Joint effect analysis found significant genetic-dosage effects for longitudinal changes in processing speed (Ptrend = 1.5 × 10-10) and executive function (Ptrend = 2.1 × 10-11). In multivariable analyses, predictors of NCF decline included progressive disease, lower baseline NCF performance, and more at-risk genetic variants, after adjusting for age, sex, education, tumor location, histology, and disease progression. Our longitudinal analyses revealed that polymorphisms in telomerase, DNA repair, and cognitive pathways are independent predictors of decline in NCF in glioma patients.

Neurocognitive and psychological functioning of pediatric brain tumor patients undergoing proton beam therapy for three different tumor types.

A high proportion of pediatric patients with brain tumors (BTs) are known to experience a decline in neurocognitive function after treatment. We prospectively examined neuropsychological functioning of patients with BTs of varying tumor types at different time points before, during, and after proton beam therapy. A total of 98 patients with posterior fossa tumors (PFTs; n=33), germ cell tumors (GCTs; n=52), and other supratentorial tumors (STTs; n=13) underwent baseline neuropsychological assessments and 57 patients underwent follow-up assessments. All groups displayed significantly lower performance intelligence quotient (PIQ) and processing speed (PS) scores than the normative means at baseline. The PFT group exhibited significantly lower scores for full-scale IQ, PIQ, PS, attention, and executive function. The GCT group displayed full-scale IQ scores within the normal range, but a significantly high proportion had memory deficits. In the STT group, all functions except for the PIQ and PS were intact. Longitudinal evaluations demonstrated stable global IQ scores over time in all groups. In the PFT group, verbal comprehension, attention, and PS improved over time. However, in the GCT group, verbal IQ scores declined significantly and psychological problems worsened over time, which were correlated with poorer neurocognitive function at 3-5years after treatment. In the STT group, no significant changes were observed. Because patients with BTs exhibit various types of neurocognitive deficit before radiotherapy, early cognitive treatment tailored to the tumor type maybe beneficial. Interventions for psychological problems and memory function may be necessary, especially for patients with GCT.

CNTM-04. Alterations in structural connectomic properties associated with neurocognitive changes following glioma resection

Abstract BACKGROUND Patients with brain tumors often experience decline in neurocognitive functioning (NCF) following surgical tumor resection. Connectomic studies have begun to uncover how abnormalities to underlying cerebral networks contribute to NCF deficits; however, few studies have investigated relationships between pre- to postoperative changes in structural connectomics and NCF. METHODS Fifteen right-handed adults with left perisylvian tumors underwent MRI of the brain with diffusion tensor imaging (DTI) and neuropsychological assessment before and after awake tumor resection. Graph theoretical analysis was applied to DTI-derived connectivity matrices to calculate structural network properties. Structural network properties and NCF measures were compared across the pre- to postoperative periods with matched pairs Wilcoxon signed-rank tests. Associations between pre- to postoperative change in network properties and change in NCF were determined with Spearman rank-order correlations (ρ). RESULTS Nearly 90% of the sample showed postoperative decline on 1 or more NCF measures. Significant postoperative NCF decline was found across measures of verbal memory, processing speed, executive functioning, receptive language, and the Clinical Trial Battery Composite (CTB COMP) index. Regarding connectomic properties, significant postoperative changes were observed in global and local efficiency, characteristic path length, clustering coefficient, betweenness centrality, and assortativity, with medium effect sizes. Significant associations (ρ = .59 to .62, all p &amp;lt; .05) were observed between changes in aspects of NCF and connectomic properties. CONCLUSIONS Decline in NCF was common following resection and some postoperative outcomes were associated with changes in structural connectomic properties following surgery.

Glycemic control is not associated with neurocognitive decline after cardiac surgery.

Whether perioperative glycemic control is associated with neurocognitive decline (NCD) after cardiac surgery was examined. Thirty patients undergoing cardiac surgery utilizing cardiopulmonary bypass (CPB) were screened for NCD preoperatively and on postoperative day 4 (POD4). Indices of glucose control were examined. Serum cytokine levels were measured and human transcriptome analysis was performed on blood samples. Neurocognitive data are presented as a change from baseline to POD4 in a score standardized with respect to age and gender. A decline in neurocognitive function was identified in 73% (22/30) of patients on POD4. There was no difference in neurocognitive function between patients with elevated HbA1c levels preoperatively (p = .973) or elevated fasting blood glucose levels the morning of surgery (>126 mg/dl, p = .910), or a higher maximum blood glucose levels during CPB (>180 mg/dl, p = .252), or higher average glucose levels during CPB (>160 mg/dl, p = .639). Patients with postoperative leukocytosis (WBC ≥ 10.5) had more NCD when compared to their baseline function (p = .03). Patients with elevated IL-8 levels at 6 h postoperatively had a significant decline in NCD at POD4 (p = .04). Human transcriptome analysis demonstrated unique and differential patterns of gene expression in patients depending on the presence of DM and NCD. Perioperative glycemic control does not have an effect on NCD soon after cardiac surgery. The profile of gene expression was altered in patients with NCD with or without diabetes.

Dural AV fistula - A cause of reversible dementia

DAVF is an abnormal connection between arteries and veins, where blood is supplied to DAVFs mainly through branches arising from the external carotid artery. Common symptoms are headache, orbital bruit, pulsatile tinnitus, and ophthalmoplegia and acute intracranial hemorrhage. There are only a few reports of DAVFs presenting with dementia syndrome, and a decline in neurocognitive function.

Rapidly progressive dementia and Parkinsonism as the first symptoms of dural arteriovenous fistula. The Sapienza University experience and comprehensive literature review concerning the clinical course of 102 patients

BackgroundDementia is a chronic loss of neurocognitive function that is progressive and irreversible. Dural arteriovenous fistulas (DAVFs) are acquired lesions that account for 10–15% of intracranial vascular malformations that could present with a rapid decline in neurocognitive function with or without Parkinson-like symptoms and evolve in a rapidly progressive dementia (RPD). Often the DAVFs are not even included in the differential hypotheses of this type of dementia and are not present in any type of diagnostic algorithm for evaluating RPD. MethodsWe performed a systematic review of the international literature and adding the cases coming from our institutional experience and we have collected all the reported cases of DAVFs that debut with ROD identifying the most frequent forms in terms of location and type, reporting the neurological characteristics and the outcome of each patient. ResultsThe exact pathogenesis for developing dementia in patients with DAVFs remains largely unknown. The imaging changes and pathologic findings support the hypothesis that the clinical course results from the delivery of excessive volumes of blood flow into a venous system with outflow obstruction and venous congestion. The large variety of clinical manifestations of DAVFs depends on its location but this is not exactly valid for the onset of dementia. It supposed that the highly variable clinical manifestation of DAVFs has been convincingly related to the pattern of venous drainage more than location. ConclusionsNeurologists and clinicians generally are familiar with the differential diagnoses of slowly progressive neurodegenerative dementias, but the diagnosis of RPD entails a different diagnostic approach. Due to their curable nature, the diagnosis of DAVFs must be suspected when facing a RPD picture, even more so if it is associated with characteristic abnormalities of the hemispheric white matter.

Assessment of neurocognitive function in association with WHO grades in gliomas

ObjectiveHigh-grade gliomas are fast-growing and may exhibit more severe neurocognitive function (NCF) decline compared with low-grade gliomas. A comprehensive understanding of the NCF in patients with glioma may be critical for developing effective glioma treatments and rehabilitation interventions. This study evaluated NCF more comprehensively in patients with glioma using the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) and the Wechsler Memory Scale-Revised (WMS-R), and also determined the differences in NCF in relation with the WHO grades of gliomas. MethodsThirty-five patients with newly diagnosed glioma were reviewed in the present study. The patients were divided into three groups, Grade II, III, and IV, based on the World Health Organization’s classification of tumors of the central nervous system. NCF was assessed using the WAIS-III and WMS-R. ResultsThere were 14 (40.0%), 7 (20.0%), and 14 (40.0%) patients in the grade II, grade III, and grade IV groups, respectively. The results of the Kruskal-Wallis test showed significant differences in all the scores of the WAIS-III and WMS-R between grade II and grade IV. The scores of the WAIS-III and WMS-R in grade IV patients were borderline for NCF disorders, except in the attention/concentration domain. On the other hand, grade II and III groups had normal scores. ConclusionTherefore, patients with a grade IV glioma presented NCF decline compared to grade II and III glioma. In contrast, the results of the WAIS-III and WMS-R indicated that the NCF of patients with grades II and III glioma was intact.

The 5xFAD Mouse Model of Alzheimer's Disease Displays Early Stunting of Neuronal Development in the Dentate Gyrus: a Potential Novel Treatment Window for Dementias Associated with Amyloidosis?

Approximately 5.8 million people over the age of 65 are living with Alzheimer's Disease (AD), and the number of individuals afflicted with AD is projected to double by 2050. Hallmarks of AD are intraneural plaques of amyloid-beta and neurofibrillary tangles with concomitant and progressive decline in neuro-cognitive function. Currently, there is no cure for AD, which stems partly from the sporadic nature of the disease and “after-the-fact” treatments which have failed to remediate disease progression. The goal of our lab is to elucidate early markers of AD onset prior to overt disease occurrence. To this end, we are using the 5XFAD transgenic mouse model which displays an aggressive form of amyloidosis and associated dementias, which develop because of insertion of the five most common genetic mutations associated with aberrant amyloid processing found in AD. Typically, intraneural amyloid plaques develop at 2-4 months of age in 5xFAD mice and cognitive deficits are observed at 4 to 6 months of age. The objective of our current study was to determine characteristics of hippocampal neuronal arborization in 5xFAD mice and non-transgenic (WT) littermates at at 15 days, 1-month, and 3-months of age, which is thought to be a pre-symptomatic period. Mice were euthanized in strict accordance with AALAC guidelines and approved protocols. Isolated brains from male and female 5xFAD and WT mice were fixed and Golgi stained (Rapid Stain Golgi kit, FDNeurotechnologies). Fixed tissue was sectioned by a cryostat (100 um), and slides were imaged using a Leica DM6000 at 40X. Images were then reassembled in Z-stacks and analyzed with FIJI. A Sholl analysis was performed on the hippocampal subregions of the dentate gyrus (DG), cortical area 1 (CA1), and cortical area 3 (CA3) where dendritic length was the primary endpoint. Results showed that there was no shortening at 15 days and 3-months in 5XFAD versus WT, but there was a shortening of neurites in the 5XFAD versus WT at 1-month of age, mainly within the DG (p = 0.04969; N = 6). At 1-month, the dentate gyrus neurons were 108.2μm (p = 0.04969; N = 6), or 5% shorter, with observed simplification of arborization. The other hippocampal subregions did not display significant alterations in neuronal development. These results show that at an extreme early age, 5xFAD mice already show a lack of neuronal development that occurs prior to intraneuronal amyloid plaque appearance, especially in a hippocampal subregion known to be vulnerable to AD-related neuronal loss. This subregion is especially vulnerable due to the fact that amyloid beta accumulates in this region initially, which could lead to the noted shortening in neuronal length. The DG receives input from the entorhinal cortex and is relayed to CA3 via mossy fibers, which is imperative for long-term potentiation and spatial memory. This suggests that the so-called pre-symptomatic period will have to be re-evaluated. Furthermore, our data suggest that a potential window for treatments have been found which may aid in developing novel therapeutic regimens to slow or prevent progression of AD symptomology associated with amyloidosis.

The Hippocampus: A New Organ at Risk for Postoperative Radiation Therapy for Bucco-alveolar Cancer? A Dosimetric and Biological Analysis

PurposeA significant proportion of patients with bucco-alveolar cancer are long-term survivors, warranting attention to survivorship issues. Decline in neurocognitive function after cranial irradiation for brain tumors correlates with a hippocampal maximum dose (Dmax) of more than 16 Gy, minimum dose (Dmin) of more than 9 Gy, and dose to 40% of the hippocampal volume (D40%) exceeding 7.3 Gy in 2-Gy equivalent dose (EQD2), respectively. We analyzed the utility of sparing the hippocampus in postoperative radiation therapy (PORT) for patients with bucco-alveolar cancer, given the proximity of target volumes to the hippocampus, by virtue of inclusion of the infratemporal fossa. Methods and MaterialsWe instituted hippocampal sparing for patients with bucco-alveolar cancer receiving PORT in March 2018. Ten prior and 10 subsequent consecutive patients with pathologically staged I-IVA cancers of the buccal mucosa, alveolus, and retromolar trigone formed the control group (no hippocampal sparing) and the study group (hippocampal sparing), respectively. The brain and temporal lobes were prescribed dose constraints in both groups. Patients received doses of 60 to 66 Gy at 2 Gy per fraction using the image-guided intensity modulated radiation therapy / volumetric modulated arc therapy technique. Treatment plans were evaluated for (1) hippocampal dosimetric parameters, (2) planning target volume dosimetry and plan-quality indices, and (3) biological indices of equivalent uniform dose (EUD) and normal-tissue complication probability (NTCP) for impaired neurocognitive function. ResultsHippocampal sparing significantly reduced the hippocampal DmaxEQD2, DmeanEQD2, and D40%EQD2 from 27 Gy to 10.9 Gy (P = .002), 14.3 Gy to 6.4 Gy (P = .002), and 15.5 Gy to 6.6 Gy (P = .005), respectively, with comparable plan-quality indices. The radiobiologically robust endpoints of ipsilateral hippocampal EUD (P = .005) and NTCP (P = .01) were statistically significantly improved. ConclusionsMeaningful dosimetric benefit, corroborated with radiobiological indices, was observed with hippocampal sparing. The feasibility and benefit of hippocampal sparing supports our view that the hippocampus should be incorporated as an organ at risk and attention should be given to neurocognitive function in patients with bucco-alveolar cancer who are receiving PORT.

The Effect of Hippocampal Avoidance Whole Brain Radiotherapy on the Preservation of Long-Term Neurocognitive Function in Non-Small Cell Lung Cancer Patients With Brain Metastasis.

Whole-brain radiotherapy (WBRT) is the mainstay of therapy in treating cancer patients with brain metastases, but unfortunately, it might also lead to decline in neurocognitive function. This study aims to investigate the preservation of long-term neurocognitive function in patients after hippocampal avoidance whole-brain radiotherapy (HA-WBRT). Retrospectively, 47 patients diagnosed with brain metastases of non-small cell lung cancer (NSCLC) between 2015-01-01 and 2017-12-31 at the Department of Oncology, XXX Hospital were selected and divided into 2 groups. Group A (n = 27) received HA-WBRT, whereas group B (n = 20) received WBRT. Neurocognitive function was analyzed at baseline and at 3, 6, 9, 12 and 24 months after radiotherapy, using Mine-Mental State Examination (MMSE) scales and Montreal Cognitive Assessment (MoCA) scales. The OS, PFS and tumor recurrence sites were also analyzed. When evaluated at 12 and 24 months after radiotherapy, the cognitive function scores of the hippocampal avoidance group were significantly higher than those of the non-hippocampal avoidance group (P < 0.001). In terms of patient survival, there was no significant difference in OS (P = 0.2) and PFS (P = 0.18) between these 2 groups. Fourteen patients in group A and 12 patients in group B had brain tumor recurrence after radiation, only one patient in group A occurred within 5 mm from the edge of the hippocampus (P > 0.05). In conclusion, HA-WBRT might have a protective effect on long-term neurocognitive function and did not affect patient survival.

Pre-operative Neurocognitive Function Was More Susceptible to Decline in Isocitrate Dehydrogenase Wild-Type Subgroups of Lower-Grade Glioma Patients.

Background: Neuropsychological deficits frequently occur in diffuse lower-grade glioma (DLGG) patients, but their relationship with molecular subgroups based on the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) is unclear.Methods: All patients enrolled for this study were divided into different subgroups according to the molecular-integrated 2016 CNS WHO and morphology-centric 2007 CNS WHO to compare their neurocognitive function (NCF) dysfunction. Univariate and multivariate analyses were used to assess the independent factors for NCF decline. The performance of NCF changes for discrimination of IDH and 1p19q status was evaluated by receiver operating characteristic (ROC).Results: There was no significant difference in the clinical characteristics among the molecular and morphologic subgroups. In the molecular subgroups, significant differences in NCF alterations were found in terms of attention function, working memory and executive function in grade II glioma patients; in addition to these changes in NCF, memory function and abstract thinking were also significantly different in grade III glioma patients. The pairwise comparison further confirmed that patients with astrocytoma (A)/anaplastic astrocytoma (AA) with isocitrate dehydrogenase wild-type (IDHwt) glioma were more susceptible to severe cognitive decline in terms of the NCF performance described above. For the morphologic subgroups, only working memory was significantly different in grade III glioma patients. The distribution proportion was significantly different among each subgroup of DLGG (grade II, P = 0.001; grade III, P = 0.002). The proportion of extensive NCF decline (≥5 tests) was 4, 12, and 50% in the IDH mutant oligodendroglioma (IDHm-O), IDHm-A, and IDHwt-A subgroups, and this proportion was 33, 60, and 93% in the IDHm-AO, IDHm-AA, and IDHwt-AA subgroups, respectively. In multivariate regression analysis, molecular types were independent factors for NCF alterations after adjusted the factors of tumor and demographics (p < 0.05). ROC curves suggested combined NCF tests model showed an advantage in the differentiation of IDH status.Conclusions: NCF alteration is closely related to molecular-integrated subgroups with varying degrees and frequencies in DLGG. Patients with IDHwt gliomas are more susceptible to suffer from severe and extensive NCF decline than other subgroups.

A Novel Endovascular Technique for Recanalization of Carotid Artery Chronic Total Occlusion: Staged Carotid Angioplasty and Stenting

AimSymptomatic carotid artery chronic total occlusion (SCACTO) can lead to neurocognitive function decline and carries a high risk or recurrent stroke. The treatment option is limited, endovascular intervention may be an alternative treatment but still controversial. To our knowledge, the staged carotid angioplasty and stenting (SCAS) did not previously reported. The purpose of this study was to report our experiences in this novel technique. MethodsIn 2017–2018, we attempted the staged carotid angioplasty and stenting (SCAS) approach in 13 patients who received SCACTO treatment. The SCAS approach involves two stages of intervention. The first stage involves initial recanalization and initial small-sized balloon angioplasty. The second stage, which is performed 4–6 weeks later, involves angioplasty and carotid stent placement. ResultsThe success rate of SCAS was 76.9%. At the second stage, the lumen remained patent in all the patients. The mean spontaneous increase in lumen diameter after 4–6 weeks was 51.7%. The median length of the stent was 4.0 cm, and the median number of stents used was 1. One patient had a complication of dissection, with a complication rate of 7.6%. ConclusionsSCAS is a novel technique in the endovascular treatment of SCACTO. It is a feasible and safe approach that could reduce the complication rate and number of carotid stents needed.

Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging (HIPPORAD) \u2013 a phase II prospective randomized multicenter trial (NOA-14, ARO 2015\u20133, DKTK-ROG)

BackgroundWhole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB).MethodsThis is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter.DiscussionThis is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases.Trial registrationThe HIPPORAD trial is registered with the German Clinical Trials Registry (DRKS00004598, registered 2 June 2016).

DaroACT: Darolutamide and enzalutamide effects on physical and neurocognitive function and daily activity in patients with castration-resistant prostate cancer (CRPC).

TPS5587 Background: The androgen receptor inhibitors (ARIs) apalutamide and enzalutamide (Enza) are approved for the treatment of men with advanced prostate cancer. These ARIs are associated with adverse events (AEs) including fatigue, neurocognitive dysfunction, and falls. Darolutamide (Daro) is a structurally distinct ARI approved by the FDA to treat nonmetastatic CRPC, based on significantly improved metastasis-free survival vs placebo in the ARAMIS Phase III clinical trial. Daro was not associated with a significant increase in AEs beyond that of concomitant androgen deprivation therapy, compared with placebo. DaroAcT is the first prospective trial to compare the effects of Daro to those of Enza on physical and neurocognitive function, and daily physical activity, in men with CRPC. Methods: This randomized, open-label, multicenter, Phase IIb trial (NCT04157088), involving ~20 sites across the US, is open for enrollment. After a lead-in phase of 30 pts treated with Daro alone, approximately 120 pts will be randomized 1:1 to receive Daro (600 mg twice daily) or Enza (160 mg once daily). Eligibility criteria include CRPC (metastatic and non-metastatic); age ≥18 years; Karnofsky performance status ≥80; no prior abiraterone within 6 months of enrollment, and no prior immunotherapy or apalutamide. All patients will continue luteinizing hormone-releasing hormone agonist or antagonist treatment for the duration of the study. The primary endpoint is the proportion of pts with slowed Timed Up and Go (TUG) time during the 24-week period from baseline. Secondary endpoints include the proportion of pts with worsening in short Physical Performance Battery (sPPB), mean change from baseline in daily physical activity, the proportion of pts with a decline in neurocognitive function or worsening of fatigue, and AEs. This study uses objective measures to assess physical function, including TUG and sPPB, measurements of daily activity levels with an accelerometry device for ≥7 days at designated time points, and neurocognitive tests. Fatigue is measured using the Brief Fatigue Inventory. Primary completion is estimated to be December 31, 2022. Clinical trial information: NCT04157088 .

Assessment of fatigue severity and neurocognitive functions in the real setting of Ramadan in patients with type 2 diabetes mellitus

ObjectivesType 2 diabetes mellitus (T2DM) is linked with a risk of dementia and decline in neurocognitive function. The current observational case-control study was conducted to evaluate the effect of fasting during Ramadan on cognitive functions and fatigue severity in T2DM patients using the Cambridge Neuropsychological Test Automated Battery (CANTAB). MethodsThis research was conducted at King Saud University Medical city, on 82 subjects including 43 control and 39 T2DM patients of both genders. The standardized Fatigue Severity Scale (FSS) and tests from CANTAB, including the Motor Screening Task (MOT), Spatial Span (SSP) and Intra-Extra Dimensional Set Shift (IED) were recorded during 3rd week and 2–3 weeks after Ramadan under controlled environmental conditions. Neurocognitive functions were recorded through CANTAB. ResultsIED errors (24.43 vs 50.73, p = 0.007), MOT mean and median latency (1466.32 vs 1120.27, p = 0.002) were significantly higher in T2DM than controls. IED stages completed (7.43 vs 8.69, p = 0.003) and SSP Span length were significantly lower in T2DM than controls (4.13 vs 4.82, p = 0.059). The significant differences between T2DM patients and controls persisted in the post. T2DM patients made more errors and completed less IED stages than did the controls, indicating that a worsened flexibility of attention relative to controls. Moreover, T2DM patients exhibited longer latencies in MOT, indicating poor motor performance. A comparison of performances by T2DM patients on FSS and CANTAB during and after Ramadan showed that fasting substantially increased fatigue scales, motor performance, and working-memory capacity. ConclusionsPatients with T2DM have impaired cognitive functions including poor motor performance, low flexibility of attention, and poor working memory capacity compared to healthy control subjects during and also in post Ramadan period. However, there is no clear statistical evidence that the cognitive functions (except for SSP SL scores) and fatigue severity of T2DM subjects differ between Ramadan and after Ramadan in both T2DM and controls.

Lower preoperative hematocrit, longer hospital stay, and neurocognitive decline after cardiac surgery

BackgroundCardiopulmonary bypass may be associated with postoperative neurocognitive dysfunction; however, risk factors have not been clearly identified. We hypothesize that lower hematocrit levels are correlated with postoperative neurocognitive dysfunction. MethodsA total of 30 patients underwent cardiac operations utilizing cardiopulmonary bypass and screening for neurocognitive dysfunction preoperatively and on postoperative day 4. Patients were analyzed according to hematocrit preoperatively, 6 hours postoperatively, and on postoperative day 4, and whether they received intra or postoperative transfusions of packed red blood cells. Neurocognitive data is presented as a difference in Repeatable Battery for the Assessment of Neuropsychological Status standardized score from baseline to postoperative day 4 and analyzed by unpaired two-tailed Spearman test and unpaired Mann-Whitney U test. ResultsThere was a significant correlation between patients with lower hematocrit before surgery and a decline in neurocognitive function at postoperative day 4 (P < .05). All patients experienced a decrease in hematocrit during their hospital stay, but the hematocrit 6 hours postoperatively and postoperative day 4 did not impact cognition. Receiving a transfusion was also not associated with neurocognitive dysfunction. Patients with low hematocrit preoperatively had a consistently lower hematocrit throughout their stay. Prolonged total length of stay was also significantly associated with neurocognitive decline. ConclusionA lower preoperative hematocrit and prolonged length of hospital stay are correlated with neurocognitive decline after cardiac surgery utilizing cardiopulmonary bypass.

Impact of Early Prophylactic Cranial Irradiation With Hippocampal Avoidance on Neurocognitive Function in Patients With Limited Disease Small Cell Lung Cancer. A Multicenter Phase 2 Trial (SAKK 15/12)

Our purpose was to evaluate neurocognitive function (NCF) and clinical outcomes after early hippocampal avoidance (HA) prophylactic cranial irradiation (PCI) in limited disease (LD) small cell lung cancer (SCLC). In a phase 2 trial, patients with LD SCLC received HA-PCI concomitant with the second cycle of chemotherapy and thoracic radiation therapy. All patients underwent objective NCF testing at baseline, 6 weeks, and 6 and 12 months after HA-PCI. NCF tests included Hopkins Verbal Learning Test Revised, Controlled Oral Word Association, and Trail Making Tests A and B. The primary endpoint was NCF decline at 6 months after HA-PCI. We assumed ≤30% of patients with no NCF decline to be unpromising. Secondary endpoints included brain metastases-free survival (BMFS), overall survival (OS), and safety of the concomitant treatment. Among the 44 patients enrolled in the trial, 38 had evaluable NCF assessment at 6 months after HA-PCI. The proportion of evaluable patients showing no NCF decline at 6 and 12 months was 34.2% (90% confidence interval [CI], 21.6-48.8) and 48.5% (95% CI, 30.8-66.5), respectively. Median follow-up was 13.2 months (95% CI, 12.6-14.1). At 12 months, BMFS was 84.2% and OS was 87.7% (95% CI, 73.0-94.7). Four patients died of SCLC, 1 of respiratory failure, 1 of hemorrhage, and 1 for unknown reason. The most frequently reported grade ≥3 acute adverse events were anemia (21.4%), febrile neutropenia (19.1%), and fatigue (14.3%). The proportion of patients showing no NCF decline 6 and 12 months after early HA-PCI does not appear to be better than, but rather similar to, that observed in patients receiving sequential PCI without HA. Early HA-PCI in LD SCLC is feasible, with observation of promising BMFS and OS in this selected population.