Decline In Neurocognitive Function Research Articles

Efficacy and safety evaluation of combined therapies incorporating whole-brain radiotherapy in patients with brain metastases: a systematic review and meta-analysis.

Whole-brain radiotherapy (WBRT) is a standard and effective approach for brain metastases, but it is linked to neurocognitive complications, specifically issues related to the hippocampus. Innovative strategies are being explored to enhance outcomes. However, a consensus is yet to be reached in this field. Our aim is to investigate the efficacy and safety of WBRT combined with simultaneous integrated boost (SIB), memantine, and hippocampal avoidance (HA) techniques in treatment of brain metastases. In this systematic review and meta-analysis, we comprehensively searched PubMed, MEDLINE, Embase, and Cochrane for studies reporting the efficacy and toxicity of WBRT-based combination therapies from inception to September 19, 2023. Data were pooled using random-effects models. Results were reported as risk ratios (RRs) and risk differences (RDs) for dichotomous outcomes, along with their 95% confidence intervals (CIs). Heterogeneity was evaluated using the I2 statistic. Among 2175 articles, 29 studies involving 3460 patients were included. The meta-analysis revealed that compared to WBRT alone, combination therapies significantly mitigated neurocognitive function decline (RD = -0.09, 95% CI [-0.18-0.01]; P = 0.03) and intracranial control failure (RR = 0.86, 95% CI [0.52-1.44]; P = 0.02), without increasing the risk of hippocampal recurrence or high-grade toxicities. Notably, HA-WBRT + SIB/memantine demonstrated improved neurocognitive outcomes and survival benefits. WBRT-based combination therapies demonstrate improved efficacy and comparable safety to WBRT alone, with specific emphasis on the effectiveness of HA-WBRT + Memantine and HA-WBRT + SIB in optimizing therapeutic outcomes for brain metastases.

Bridging Gaps in Sleep Health and Dementia: Linking Sleep Disorders and Neurocognitive Health

There is growing evidence of a bidirectional relationship between sleep disturbances and disorders and cognitive function in normal and pathological aging. Not only do sleep disturbances and disorders predict and contribute to a decline in neurocognitive function, but neurodegenerative disorders impair sleep. Furthermore, sleep and rhythm disturbances may be some of the earliest symptoms of neurodegenerative disorders such as MCI, AD, and Parkinson's disease. However, the potential effects of improving sleep on mitigating decline in cognitive function are still unknown. While some of the classes of pharmaceutical agents may improve subjective sleep, they have variable effects on sleep oscillations and cognition. The effects of other approaches, such as cognitive behavioral therapy and neuromodulation, on neurodegenerative processes are not yet fully understood.The goal of this session and panel is to educate participants about changes in sleep patterns and sleep oscillations that occur in aging and neurodegenerative disorders, mechanisms for associations between poor sleep and sleep disorders and cognitive decline and contribution to dementia, and the potential benefits of identifying and treating sleep disorders in older adults who may be at risk of developing dementia. In addition, the discussion will highlight the lack of standardized care pathways for diagnosing and treating sleep problems in older adults.

Post-operative cognitive dysfunction is exacerbated by high-fat diet via TLR4 and prevented by dietary DHA supplementation

Post-operative cognitive dysfunction (POCD) is an abrupt decline in neurocognitive function arising shortly after surgery and persisting for weeks to months, increasing the risk of dementia diagnosis. Advanced age, obesity, and comorbidities linked to high-fat diet (HFD) consumption such as diabetes and hypertension have been identified as risk factors for POCD, although underlying mechanisms remain unclear. We have previously shown that surgery alone, or 3-days of HFD can each evoke sufficient neuroinflammation to cause memory deficits in aged, but not young rats. The aim of the present study was to determine if HFD consumption before surgery would potentiate and prolong the subsequent neuroinflammatory response and memory deficits, and if so, to determine the extent to which these effects depend on activation of the innate immune receptor TLR4, which both insults are known to stimulate. Young-adult (3mo) & aged (24mo) male F344xBN F1 rats were fed standard chow or HFD for 3-days immediately before sham surgery or laparotomy. In aged rats, the combination of HFD and surgery caused persistent deficits in contextual memory and cued-fear memory, though it was determined that HFD alone was sufficient to cause the long-lasting cued-fear memory deficits. In young adult rats, HFD + surgery caused only cued-fear memory deficits. Elevated proinflammatory gene expression in the hippocampus of both young and aged rats that received HFD + surgery persisted for at least 3-weeks after surgery. In a separate experiment, rats were administered the TLR4-specific antagonist, LPS-RS, immediately before HFD onset, which ameliorated the HFD + surgery-associated neuroinflammation and memory deficits. Similarly, dietary DHA supplementation for 4 weeks prior to HFD onset blunted the neuroinflammatory response to surgery and prevented development of persistent memory deficits. These results suggest that HFD 1) increases risk of persistent POCD-associated memory impairments following surgery in male rats in 2) a TLR4-dependent manner, which 3) can be targeted by DHA supplementation to mitigate development of persistent POCD.

Reprimo (RPRM) as a Potential Preventive and Therapeutic Target for Radiation-Induced Brain Injury via Multiple Mechanisms.

Patients receiving cranial radiotherapy for primary and metastatic brain tumors may experience radiation-induced brain injury (RIBI). Thus far, there has been a lack of effective preventive and therapeutic strategies for RIBI. Due to its complicated underlying pathogenic mechanisms, it is rather difficult to develop a single approach to target them simultaneously. We have recently reported that Reprimo (RPRM), a tumor suppressor gene, is a critical player in DNA damage repair, and RPRM deletion significantly confers radioresistance to mice. Herein, by using an RPRM knockout (KO) mouse model established in our laboratory, we found that RPRM deletion alleviated RIBI in mice via targeting its multiple underlying mechanisms. Specifically, RPRM knockout significantly reduced hippocampal DNA damage and apoptosis shortly after mice were exposed to whole-brain irradiation (WBI). For the late-delayed effect of WBI, RPRM knockout obviously ameliorated a radiation-induced decline in neurocognitive function and dramatically diminished WBI-induced neurogenesis inhibition. Moreover, RPRM KO mice exhibited a significantly lower level of acute and chronic inflammation response and microglial activation than wild-type (WT) mice post-WBI. Finally, we uncovered that RPRM knockout not only protected microglia against radiation-induced damage, thus preventing microglial activation, but also protected neurons and decreased the induction of CCL2 in neurons after irradiation, in turn attenuating the activation of microglial cells nearby through paracrine CCL2. Taken together, our results indicate that RPRM plays a crucial role in the occurrence of RIBI, suggesting that RPRM may serve as a novel potential target for the prevention and treatment of RIBI.

Using artificial intelligence (AI) to predict the conversion of cognitively unimpaired individuals to mild cognitive impairment

AbstractBackgroundMild cognitive impairment (MCI) is the objective decline in neurocognitive functioning, but without significant impairment of the individual’s ability to perform the usual instrumental activities of daily living (1). Diagnosing MCI can be done using a combination of different methods such as cognitive testing, structural neuroimaging, nuclear imaging, and cerebrospinal fluids, and plasma biomarkers. Some of these methods are invasive and expensive. Machine learning (ML) algorithms can be trained to predict the onset of MCI, using data from non‐invasive methods.MethodFour databases (WoS, MEDLINE, EMBASE, and CINAHL) were searched using search string of relevant terms (cognitive decline, artificial intelligence, prediction, and cognitively unimpaired). Articles that reportedtrained ML algorithms using non‐invasive predictors of MCI in cognitively healthy adults (≥ 18 years old) were included. The review was registered with PROSPERO (CRD42022379027) and PRISMA guidelines were followed. The Newcastle‐Ottawa Quality Assessment scale was used to assess the quality of studies.ResultOf the 1,098 articles identified and screened, 22 studies were included. 373 non‐invasive predictors of MCI were identified. The most prevalent predictors included: demographic information (age, sex, years in education), voice and speech parameters (sentence repeating, semantic fluency), gait parameters (velocity, cadence, step time), performance on cognitive tests (MMSE, K‐MoCA, CDR, AD8), eye‐movements (pupil diameter, saccade orientation) and Instrumental activity of daily livings (medication, finance management). The maximum and minimum number of predictors used to develop a ML algorithm was 121 and 2, respectively. The ML algorithms developed in the included studies had (average sensitivity and specificity of 77.90%±22 and 80.84%±18, respectively) exceeded the performance of algorithms that used invasive and expensive predictors such as nuclear imaging and neuroimaging which achieved accuracy scores (60%‐77%) (2).ConclusionNon‐invasive predictors can be used to train ML algorithms to predict the onset of MCI in cognitively healthy individuals with good accuracy scores exceeding 70%. These algorithms may can aid clinician decision making, thus setting early treatment plans, and allowing individuals to be involved in care planning before progression of MCI to dementia AD.

Impact of Apolipoprotein E Genotype on Neurocognitive Function in Patients With Brain Metastases: An Analysis of NRG Oncology's RTOG 0614

Whole-brain radiation therapy (WBRT) is a common treatment for brain metastases and is frequently associated with decline in neurocognitive functioning (NCF). The e4 allele of the apolipoprotein E (APOE) gene is associated with increased risk of Alzheimer disease and NCF decline associated with a variety of neurologic diseases and insults. APOE carrier status has not been evaluated as a risk factor for onset time or extent of NCF impairment in patients with brain metastases treated with WBRT. NRG/Radiation Therapy Oncology Group 0614 treated adult patients with brain metastases with 37.5 Gy of WBRT (+/- memantine), performed longitudinal NCF testing, and included an optional blood draw for APOE analysis. NCF test results were compared at baseline and over time with mixed-effects models. A cause-specific Cox model for time to NCF failure was performed to assess the effects of treatment arm and APOE carrier status. APOE results were available for 45% of patients (n = 227/508). NCF did not differ by APOE e4 carrier status at baseline. Mixed-effects modeling showed that APOE e4 carriers had worse memory after WBRT compared with APOE e4 noncarriers (Hopkins Verbal Learning Test-Revised total recall [least square mean difference, 0.63; P = .0074], delayed recognition [least square mean difference, 0.75; P = .023]). However, APOE e4 carrier status was not associated with time to NCF failure (hazard ratio, 0.86; 95% CI, 0.60-1.23; P = .40). Memantine delayed the time to NCF failure, regardless of carrier status (hazard ratio, 0.72; 95% CI, 0.52-1.01; P = .054). APOE e4 carriers with brain metastases exhibited greater decline in learning and memory, executive function, and the Clinical Trial Battery Composite score after treatment with WBRT (+/- memantine), without acceleration of onset of difference in time to NCF failure.

Whole brain irradiation–induced endothelial dysfunction in the mouse brain

Whole brain irradiation (WBI), also known as whole brain radiation therapy (WBRT), is a well-established treatment for multiple brain metastases and as a preventive measure to reduce the risk of recurrence after surgical removal of a cerebral metastasis. However, WBI has been found to lead to a gradual decline in neurocognitive function in approximately 50% of patients who survive the treatment, significantly impacting their overall quality of life. Recent preclinical investigations have shed light on the underlying mechanisms of this adverse effect, revealing a complex cerebrovascular injury that involves the induction of cellular senescence in various components of the neurovascular unit, including endothelial cells. The emergence of cellular senescence following WBI has been implicated in the disruption of the blood-brain barrier and impairment of neurovascular coupling responses following irradiation. Building upon these findings, the present study aims to test the hypothesis that WBI-induced endothelial injury promotes endothelial dysfunction, which mimics the aging phenotype. To investigate this hypothesis, we employed a clinically relevant fractionated WBI protocol (5 Gy twice weekly for 4 weeks) on young mice. Both the WBI-treated and control mice were fitted with a cranial window, enabling the assessment of microvascular endothelial function. In order to evaluate the endothelium-dependent, NO-mediated cerebral blood flow (CBF) responses, we topically administered acetylcholine and ATP, and measured the resulting changes using laser Doppler flowmetry. We found that the increases in regional CBF induced by acetylcholine and ATP were significantly diminished in mice subjected to WBI. These findings provide additional preclinical evidence supporting the notion that WBI induces dysfunction in cerebrovascular endothelial cells, which in turn likely contributes to the detrimental long-term effects of the treatment. This endothelial dysfunction resembles an accelerated aging phenotype in the cerebrovascular system and is likely causally linked to the development of cognitive impairment. By integrating these findings with our previous results, we have deepened our understanding of the lasting consequences of WBI. Moreover, our study underscores the critical role of cerebromicrovascular health in safeguarding cognitive function over the long term. This enhanced understanding highlights the importance of prioritizing cerebromicrovascular health in the context of preserving cognitive abilities.

App-based assessment of memory functions in patients after transfemoral aortic valve replacement.

Transfemoral aortic valve replacement (TAVR) is the standard treatment for elderly patients with aortic valve stenosis. Although safe and well-established, there is a risk of intraprocedural hemodynamic instability and silent cerebral embolism, which can lead to a decline in neurocognitive function and dementia. In clinical practice, comprehensive cognitive testing is difficult to perform. AI-assisted digital applications may help to optimize diagnosis and monitoring. Neurocognitive function was assessed by validated psychometric tests using "∆elta -App", which uses artificial intelligence and computational linguistic methods for extraction and analysis. Memory function was assessed using the 'Consortium to Establish a Registry for Alzheimer's Disease' (CERAD) word list and digit span task (DST) before TAVR and before hospital discharge. The study is registered in the German Register of Clinical Trials (https://drks.de/search/de/trial/DRKS00020813). From October 2020 until March 2022, 141 patients were enrolled at University Hospital Heart Centre Brandenburg. Mean age was 81 ± 6 years, 42.6% were women. Time between the pre- and post-interventional test was on average 6 ± 3 days. Memory function before TAVR was found to be below average in relation to age and educational level. The pre-post TAVR comparison showed significant improvements in the wordlist repeat, P < 0.001 and wordlist recall test of CERAD, P < 0.001. There were no changes in the digital span test. Despite impaired preoperative memory function before TAVR, no global negative effect on memory function after TVAR was detected. The improvements shown in the word list test should be interpreted as usual learning effects in this task.

Elimination of senescent cells by treatment with Navitoclax/ABT263 reverses whole brain irradiation-induced blood-brain barrier disruption in the mouse brain.

Whole brain irradiation (WBI), a commonly employed therapy for multiple brain metastases and as a prophylactic measure after cerebral metastasis resection, is associated with a progressive decline in neurocognitive function, significantly impacting the quality of life for approximately half of the surviving patients. Recent preclinical investigations have shed light on the multifaceted cerebrovascular injury mechanisms underlying this side effect of WBI. In this study, we aimed to test the hypothesis that WBI induces endothelial senescence, contributing to chronic disruption of the blood-brain barrier (BBB) and microvascular rarefaction. To accomplish this, we utilized transgenic p16-3MR mice, which enable the identification and selective elimination of senescent cells. These mice were subjected to a clinically relevant fractionated WBI protocol (5 Gy twice weekly for 4 weeks), and cranial windows were applied to both WBI-treated and control mice. Quantitative assessment of BBB permeability and capillary density was performed using two-photon microscopy at the 6-month post-irradiation time point. The presence of senescent microvascular endothelial cells was assessed by imaging flow cytometry, immunolabeling, and single-cell RNA-sequencing (scRNA-seq). WBI induced endothelial senescence, which associated with chronic BBB disruption and a trend for decreased microvascular density in the mouse cortex. In order to investigate the cause-and-effect relationship between WBI-induced senescence and microvascular injury, senescent cells were selectively removed from animals subjected to WBI treatment using Navitoclax/ABT263, a well-known senolytic drug. This intervention was carried out at the 3-month post-WBI time point. In WBI-treated mice, Navitoclax/ABT263 effectively eliminated senescent endothelial cells, which was associated with decreased BBB permeability and a trend for increased cortical capillarization. Our findings provide additional preclinical evidence that senolytic treatment approaches may be developed for prevention of the side effects of WBI.

The Role of Estrogen Therapy as a Protective Factor for Alzheimer's Disease and Dementia in Postmenopausal Women: A Comprehensive Review of the Literature.

The complete cessation of menstruation for 12 months with associated vasomotor symptoms is termed menopause.Apart from playing a role in reproduction, estrogen significantly affects the central nervous system (CNS). Population-based studies highlighted a substantial difference in the prevalence of dementia between men and women, with Alzheimer-associated dementia being more prevalent in women, indicating that estrogen deficiency might be a risk factor for neurodegenerative diseases. Patients with dementia experience a progressive decline in neurocognitive function, beginning with short-term memory loss that progresses to long-term memory loss and the inability to perform everyday activities, leading ultimately to death.There is currently no cure for dementia, so preventing or slowing the disease's progression is paramount. Accordingly, researchers have widely studied the role of estrogen as a neuroprotective agent. Estrogen prevents dementia by augmenting Hippocampal and prefrontal cortex function, reducing neuroinflammation, preventing degradation of estrogen receptors, decreasing oxidative damage to the brain, and increasing cholinergic and serotonergic function. According to the window phase hypothesis, estrogen's effect on preventing dementia is more pronounced if therapy is started early, during the first five years of menopause.Other studies like The Woman's Health Initiative Memory Study (WHIMS) showed unfavorable effects of estrogen on the brain. This review aims to establish an understanding of the currently available data on estrogen's effect on neurodegeneration, namely, dementia and Alzheimer's disease.

Neurocognitive function outcomes in NRG/RTOG 0534, the SPPORT trial.

12022 Background: RTOG 0534 established the benefit of adding of short term androgen deprivation therapy (PBRT+STADT, Arm 2) to prostate bed salvage radiotherapy (PBRT, Arm 1), and demonstrated that elective pelvic lymph node irradiation combined with STADT (PBRT+STADT+PLNRT, Arm 3) results in further reductions in progression. Longitudinal monitoring of neurocognitive function (NCF) was conducted to evaluate the hypothesis that patients treated with STADT will demonstrate greater decline in NCF compared to patients receiving PBRT alone. Methods: Patients were administered the Clinical Trial Battery [Hopkins Verbal Learning Test – Revised (HVLT-R), Trail Making Test (TMT), and the Controlled Oral Word Association (COWA) test] by certified test administrators at baseline, and at 6 weeks (6w), 1 year (1yr), and 5 years after the end of RT (5yr). Raw NCF tests scores were converted to standardized z-scores adjusted for age and education when necessary. Analyses included z-score change and reliable change index (RCI) determined decline compared to baseline, and longitudinal mixed effect regression models using z-scores. To control for multiplicity, p &lt; 0.025 is required for statistical significance. Results: Among the 1716 analyzable patients, 429 consented to NCF monitoring. There were no significant differences in sociodemographic or clinical characteristics between arms. NCF test completion was 82, 76, 63 and 30% at baseline, 6w, 1yr, and 5yr, respectively. RCI-based NCF deterioration was more frequent in Arm 3 compared to Arm 1 at 6 weeks on Delayed Recall (16% vs. 7%, p = 0.023). Patients in Arm 3 evidenced greater z-score decline compared to patients in Arm 1 at 6w on HVLT-R Total Recall [M(SD) Z-score∆ = -0.1(1.0) vs 0.2(0.9), (p = 0.020)] and Delayed Recall [M(SD) Z-score∆ = -0.4(1.5) vs 0.1(1.2), (p = 0.012)]. Mixed effects models identified statistically significant differences in z-scores between Arm 3 and 1 at 6w on Delayed Recall [-0.541 (SE 0.178, p = 0.002)]. A statistically significant difference was observed between Arm 2 and 1 at 6w on TMTB [1.498 (SE 0.626, p = 0.017) favoring Arm 2]. Between arm differences were not seen at any other time point, or on other NCF outcomes. Conclusions: Compared to patients treated with PBRT alone, patients treated with PBRT+STADT+PLNRT exhibited greater worsening in episodic verbal learning and memory processes at 6 weeks after the end of RT, while patients treated with PBRT+STADT exhibited greater improvement in processing speed. The absence of long term or progressive cognitive decline associated with STADT-containing regimens is promising but limited by substantial missing data at year 5. FUNDING This project was supported by grants 10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), CTEP from the National Cancer Institute (NCI). Clinical trial information: NCT00567580 .

Fractionated Volumetric Modulated Arc Therapy (FVMAT) for Oligometastatic Brain Tumor

Intracranial metastasis is very common in adult cancer patients with an overall incidence of approximately 10–40%. The most common primary tumors responsible for this in adults are lung and breast cancer. Brain metastasis signifies a grave prognosis, with a median survival of 6 to 12 months. They are traditionally managed with palliative care and whole brain radiotherapy (WBRT). WBRT was an effective method to control brain metastases, decreasing corticosteroid use to control tumor-associated edema, and potentially improving overall survival; however, WBRT was found to be associated with a serious neurocognitive degeneration, this adverse effect (AE) follows a biphasic pattern beginning with a transient decline in mental functioning at around 4 months post-treatment, slowly leading to an irreversible neurologic impairment from months to years later. Evidence supports that WBRT can cause radiation injury to the hippocampus, which in turn will lead to a decline in neurocognitive function (NCF). Volumetric modulated arc therapy (VMAT) is a relatively new type of image-guided radiotherapy that treats multiple brain metastasis simultaneously and efficiently with less neurocognitive sequelae. Eighteen cancer patients with limited (≤5 brain tumors) or oligometastatic brain tumor were treated with a spatially fractionated VMAT technique for a total dose of 30 Gy in 10 fractions, the patients tolerated the VMAT treatment with no radiation-induced neurologic toxicities after a mean follow-up of 1 year. Local control rate was 84%, and the median survival for these 19 patients was 11.3 months (range: 9.1–22.4 months). In conclusion, the VMAT is a suitable technique that is a safe and effective treatment for brain oligometastases.

Diagnosis and Treatment Using Autologous Stem-Cell Transplantation in Primary Central Nervous System Lymphoma: A Systematic Review.

Consolidation therapy has improved the outcome of newly diagnosed PCNSL patients. Whole-brain radiotherapy (WBRT) was the first consolidation strategy used and represented the gold standard for many years, but at the expense of a high risk of neurotoxicity. Thus, alternative strategies are being investigated in order to improve disease outcomes and to spare the neurocognitive side effects due to WBRT. We reviewed published studies on PCNSL patients treated with HDC/ASCT, focusing on the efficacy and safety of the conditioning regimens. Prospective and retrospective studies, published in the English language from 1992 to 2022, in high-quality international journals were identified in PubMed. Consolidation with HDC containing highly CNS-penetrating agents (thiotepa, busulfan or BCNU) followed by ASCT provided long-term disease control and survival in PCNSL patients. Two prospective randomized studies, comparing HDC/ASCT versus WBRT, reported similar progression-free survival (PFS) and similar results on the decline in neurocognitive functions in a substantial proportion of patients after WBRT but not after HDC-ASCT. A recent randomized study comparing HDC/ASCT versus non-myeloablative consolidation reported a longer PFS in transplanted patients. ASCT conditioned with regimens, including highly CNS-penetrating agents, represents, to date, the best choice among the available consolidation strategies for fit newly diagnosed PCNSL patients.

Factors Associated With Neurocognitive Impairment Following Chemoradiotherapy in Patients With High-Grade Glioma: Results of a Prospective Trial.

High-grade gliomas (HGG) are highly fatal tumors despite advanced multimodality management. They are also associated with neurocognitive impairment, both due to disease pathology and treatment. We aimed to assess various risk factors responsible for neurocognitive decline in HGG patients undergoing adjuvant chemoradiation. Newly diagnosed HGG patients who underwent maximal safe resection were included. Patients received volumetric modulated arc therapy to a dose of 60 Gy in 30 fractions, along with concurrent temozolomide (TMZ) at a dose of 75 mg/m²/day orally; thereafter adjuvant TMZ (150-200 mg/m² for 5 days), given every 28 days for 6 to 8 cycles. The Mini-Mental State Examination questionnaire was used to measure cognitive impairment of each study patient at various time points. Cox regression model was used for univariate and multivariable analysis of data to establish possible risk factors. Fifty-three patients were enrolled and analyzed. At a median follow-up of 15 months, 30 patients (56.6%) developed cognitive impairment, and 23 patients (43.4%) did not. On univariate analysis, HGG with WHO grade 4, glioblastoma and diffuse midline glioma histology, IDH-wild type, recursive partitioning analysis class IV/V, and only biopsy of primary tumor were significantly associated with neurocognitive impairment, but none of them were independent risk factors on multivariable analysis. Planning target volume and dose received by ipsilateral hippocampus were also significantly correlated with cognitive decline in HGG patients. Decline in neurocognitive functions in HGG patients is multifactorial and can be attributed to an amalgam of various tumor, patient, and treatment-related factors.

RADT-24. PHASE II STUDY OF PROTON RADIATION THERAPY FOR LOWER GRADE GLIOMAS

Abstract PURPOSE To report preliminary results on outcomes of patients with lower grade gliomas (LGG) treated with proton therapy. METHODS Patients with grade II or IDH mutant grade III glioma and indications for radiation therapy were enrolled in a prospective single arm trial of proton therapy (PRT), receiving a dose of 54 Gy(RBE) or 59.4 Gy(RBE), respectively. Comprehensive baseline and regular post-treatment evaluations of neuroendocrine function, neurocognitive functions (NCF), quality of life (QOL), and progression-free survival (PFS) were performed. RESULTS Among 60 patients (median age 40.8) who received PRT, 28 (47%) were men, and 39 (65%) were WHO grade II. Eighteen patients (30%) were IDH mutant+1p/19q co-deleted, 36 (60%) were IDH mutant astrocytoma, and 6 (10%) were IDH wildtype. Treatment was at initial diagnosis (41; 68%) or progression (19; 32%). Median follow-up after PRT was 4.1 years. All current data are reported for 3 years from PRT. PFS at 3 years was 86% for all patients, 84% for grade II (n = 39), and 90% for favorable grade III gliomas (n = 21). PFS was 83% for IDH mutant astrocytoma, and 94% for IDH mutant+1p/19q co-deleted oligodendrogliomas. New endocrine dysfunction was detected in 3 patients (5%). There was one grade 4 case of brain necrosis (2%) but no grade 3 toxicities. NCF decline, defined by Z-score drop of &amp;gt;/= 1SD on clinical trials battery composite, occurred in 7% (n = 3/43). QOL assessment by FACT-Brain showed 16% with decline of &amp;gt;/= 10 points (n = 7/43). CONCLUSIONS At 3 years post-treatment, LGG patients receiving PRT have a high PFS, similarly to previous reports on photon therapy, few new neuroendocrine deficiencies, modest treatment toxicities, and minimal decline in NCF or QOL. These positive outcomes may be attributable to limited integral dose to the brain by use of PRT, demonstrating its value in treatment of LGG patients with long survival expectations.

Evaluating Heterogeneity of Hippocampal Avoidant Whole Brain Radiotherapy (HA-WBRT) Treatment Effect on Neurocognitive Function (NCF): Secondary Analysis of NRG-CC001

<h3>Purpose/Objective(s)</h3> NRG-CC001, a trial evaluating the neuroprotective effect of HA-WBRT versus standard WBRT in patients with brain metastases (BM), demonstrated a significantly lower risk of NCF decline. Given the heterogeneous BM patient population, we sought to systematically identify subgroups of patients through secondary analysis of trial data that could derive differential benefit from HA. <h3>Materials/Methods</h3> We performed a post hoc analysis of NRG-CC001, a phase III clinical trial in which 518 patients with BM were randomly assigned to WBRT plus memantine or HA-WBRT plus memantine. In this secondary analysis, cumulative incidence function (CIF) estimated NCF failure between arms and subgroups was tested using Gray's test. Covariate and subgroup association with differential treatment response was calculated using Cox proportional hazards modeling; these factors were then tested for interaction with treatment arm. <h3>Results</h3> Age (>61), education (<high school) irrespective of treatment arm were predictive of higher risk of NCF failure (p=0.005 and p=0.007, respectively). Patients living <4 months derived no benefit from HA-WBRT (Gray's test p=0.793), but for those living >=4 months, there was a significant benefit favoring HA-WBRT (p=0.03). We found evidence of heterogeneity of treatment effect based on primary tumor histology (interaction test p=0.01): primary lung histology patients (HR 0.58, 95% CI: 0.43-0.77, p=0.0007) compared to those with non-lung histology primary tumors (HR 1.15, 95% CI: 0.78-1.71, p=0.48). Baseline MD Anderson Symptom Inventory for brain tumor (MDASI-BT) cognitive factor scores were also found to be highly associated with treatment response with significance on test for interaction (p=0.03); those with MDASI-BT baseline scores in quartiles 1-3 had significantly greater differential treatment response (HR=0.64, 95% CI: 0.48-0.85, p=0.002) compared to those with the highest MDASI-BT baseline scores (HR=1.24, 95% CI: 0.76-2.04, p=0.39). There was no significant heterogeneity of treatment effect based on age, education level, and baseline KPS. <h3>Conclusion</h3> This post-hoc subgroup analysis of NRG-CC001 evaluating heterogeneity of treatment effect confirmed that the neurocognitive protective benefit of HA-WBRT was most substantial for patients living > 4 months; for those surviving <4 months, statistically significant benefit was not identified, possibly because cognitive decline post-WBRT requires a window of time to manifest. We also found that treatment response was significantly associated with several patient and tumor characteristics. Patients with lung histology as well as those with lower baseline MDASI-BT cognitive factor scores, denoting less severe cognitive impairment at enrollment, had significantly greater benefit from HA-WBRT. These data may better help clinicians decide which subgroups of patients benefit most from HA-WBRT.

Hippocampal Dosimetry and Neurocognitive Function in Patients Undergoing Stereotactic Radiosurgery for Brain Metastases

Abstract AIMS To measure neurocognitive function (NCF) and correlate with hippocampus dose in patients undergoing stereotactic radiosurgery (SRS) for 1-3 brain metastases. METHOD We conducted a prospective observational study measuring NCF before and after SRS in patients with 1-3 brain metastases and correlated changes with hippocampal dosimetry Patients underwent NCF testing at baseline, 1 month, 3 months and 6 months post SRS and quality of life was measured at each time point. NCF tests included Hopkin’s Verbal learning test, controlled oral word association test and trail making tests. Hippocampus was outlined in line with RTOG guidance and dose was collected from the treatment planning system. RESULTS 36 patients were recruited. Mean age was 64 years, median WHO performance status 1 (range 0-2). At baseline, 65% of patients displayed NCF impairment in at least 1 NCF domain and 33% didn’t exhibit any neurological symptoms. Asymptomatic patients has underlying diagnosis of non-small cell lung cancer or melanoma. NCF impairment was evident at 1, 3 and 6 months for 50%, 66% and 40% patients respectively. Decline at 1 month was associated with higher median dose to 0.1cc of hippocampus (5 Gy vs 2.35 Gy). Association with hippocampal dose and NCF impairment at 3 and 6 months was not observed. CONCLUSION A significant proportion of patients exhibited impaired NCF at baseline with greatest NCF decline seen at 1 months and subsequent recovery of NCF evident at 6 months. Dose to hippocampus 0.1cc may be associated with acute NCF toxicity. Main limitations of this study was small number of patients.

The multisystemic effects of oral appliance therapy for obstructive sleep apnea: A narrative review.

Obstructive sleep apnea (OSA) is a chronic condition accompanied by repeated obstruction of the upper airway during sleep despite respiratory efforts, resulting in intermittent hypoxemia, altered sleep structure, and sympathetic activation. Previous studies have shown a significant association between OSA and general health issues such as cardiovascular diseases, endocrine disorders, neurocognitive function decline, and poor quality of life. Continuous positive airway pressure (CPAP) has been considered as the first line treatment for OSA. However, accumulating evidence supports the role of oral appliance (OA) therapy, including mandibular advancement devices, as an alternative option for snoring and OSA patients who do not comply with or refuse CPAP usage. Despite a generally favorable outcome of OA therapy for OSA related respiratory indices, studies focusing on the impact of systemic effects of OA therapy in OSA patients are relatively scarce compared with the extensive literature focusing on the systemic effects of CPAP. Therefore, this article aimed to provide an overview of the current evidence regarding the multisystemic effects of OA therapy for OSA.

A systematic review of cognitive function after carotid endarterectomy in asymptomatic patients

Objective: Asymptomatic carotid stenosis has been associated with a progressive decline in neurocognitive function. However, the effect of carotid endarterectomy (CEA) on this process is poorly understood. We aimed to evaluate preoperative and postoperative cognitive function changes in asymptomatic patients after CEA.

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.