Alzheimer's disease biomarkers and their current use in clinical research and practice.

While blood-based tests are readily available for various conditions, including cardiovascular diseases, type 2 diabetes, and common cancers, Alzheimer's disease (AD) and other neurodegenerative diseases lack an early blood-based screening test that can be used in primary care. Major efforts have been made towards the investigation of approaches that may lead to minimally invasive, cost-effective, and reliable tests capable of measuring brain pathological status. Here, we review past and current technologies developed to investigate biomarkers of AD, including novel blood-based approaches and the more established cerebrospinal fluid and neuroimaging biomarkers of disease. The utility of blood as a source of AD-related biomarkers in both clinical practice and interventional trials is discussed, supported by a comprehensive list of clinical trials for AD drugs and interventions that list biomarkers as primary or secondary endpoints. We highlight that identifying individuals in early preclinical AD using blood-based biomarkers will improve clinical trials and the optimization of therapeutic treatments as they become available. Lastly, we discuss challenges that remain in the field and address new approaches being developed, such as the examination of cargo packaged within extracellular vesicles of neuronal origin isolated from peripheral blood.

Prospects and challenges in using neuronal extracellular vesicles in biomarker research.

Extracellular vesicles (EVs) hold promise as a source of disease biomarkers. The diverse molecular cargo of EVs can potentially indicate the status of their tissue of origin, even against the complex background of whole plasma. The main tools currently available for assessing biomarkers of brain health include brain imaging and analysis of the cerebrospinal fluid of patients. Given the costs and difficulties associated with these methods, isolation of EVs of neuronal origin (NEVs) from the blood is an attractive approach to identify brain-specific biomarkers. This perspective describes current key challenges in EV- and NEV-based biomarker research. These include the relative low abundance of EVs, the lack of validated isolation methods, and the difficult search for an adequate target for immunocapturing NEVs. We discuss that these challenges must be addressed before NEVs can fulfill their potential for biomarker research. HIGHLIGHTS: NEVs are promising sources of biomarkers for brain disorders. Immunocapturing NEVs from complex biofluids presents several challenges. The choice of surface target for capture will determine NEV yield. Contamination by non-EV sources is relevant for biomarkers at low concentrations.

Feasibility of using a transmission ion chamber for QA tests of medical linear accelerators.

PURPOSE: To study the feasibility of using the Integral Quality Monitoring (IQM) system for routine quality assurance (QA) of photon beams. METHODS: The IQM system is a commercially available dose delivery verification tool, which consists of a spatially sensitive large area transmission ion chamber, mounted on the Linac collimator, and a calculation algorithm to predict the signals in response to radiation beams. By comparing the measured and predicted signals the system verifies the accuracy of beam delivery. The ion chamber unit is a battery powered system including a dual-electrometer, temperature and pressure sensors, and inclinometers. The feasibility of using the IQM system for routine QA tests was investigated by measuring constancy values of beam parameters, with specially designed tests fields, and comparing them with those determined by a conventional system. RESULTS: The sensitivity of the beam output constancy measurements by the IQM system was found to agree with those measured by a Farmer type ion chamber placed in water phantoms to within 0.1% for typical daily output variation of ± 0.5% and ± 1%. The beam symmetry was measured with a 4 cm × 4 cm aperture at multiple off-axis distances and was found to have a highly linear relationship with those measured in a water phantom scan for intentionally introduced asymmetry between -3% and +3%. The beam flatness was measured with a two-field ratio method and was found to be linearly correlated with those measured by water phantom scan. The dosimetric equivalent of a picket fence test performed by the IQM system can serve as a constancy check of the multileaf collimator (MLC) bank positioning test. CONCLUSIONS: The IQM system has been investigated for constancy measurements of various beam parameters for photon beams. The results suggest that the system can be used for most of the routine QA tests effectively and efficiently.

Rectal ultrasound as unique diagnostic option in obstructive colorectal metastasis from breast adenocarcinoma.

We present the case of an uncommon manifestation of metastatic breast cancer as an occlusive colorectal stenosis with submucosal location. The endoscopic rectal ultrasound allowed to confirm the diagnosis with transmural biopsies.

AAPM task group report 275.S: Survey strategy and results on plan review and chart check practices in US and Canada.

BACKGROUND: AAPM Task Group (TG) 275 was charged with developing practical, evidence-based recommendations for physics plan and chart review clinical processes for radiation therapy. As part of this charge, and to characterize practices and clinical processes, a survey of the medical physics community was developed and conducted. Detailed analyses and trends based on the survey that exceeded TG report length constraints are presented herein. AIMS: The design, development, and detailed results of the TG- 275 survey as well as statistical analysis and trends are described in detail. This is complementary material to the TG 275 report. METHODS AND MATERIALS: The survey consisted of 100 multiple-choice questions divided into four main sections: 1) Demographics, 2) Initial Plan Check, 3) On-Treatment, and 4) End-of-Treatment Chart Check. The survey was released to all AAPM members who self-reported working in the radiation oncology field, and it was kept open for 7 weeks. Results were summarized using descriptive statistics. To study practice differences, tests of association were performed using data grouped by four demographic questions: 1) Institution Type, 2) Average number of patients treated daily, 3) Radiation Oncology Electronic Medical Record, and 4) Perceived Culture of Safety. RESULTS: The survey captured 1370 non-duplicate entries from the United States and Canada. Differences across practices were grouped and presented based on Process-Based and Check-Specific questions. A risk-based summary was created to show differences amongst the four demographic questions for checks associated with the highest risk failure modes identified by TG-275. CONCLUSION: The TG-275 survey captured a baseline of practices on initial plan, on-treatment, and end-of-treatment checks across a wide variety of clinics and institutions. The results of test of association showed practice heterogeneities as a function of demographic characteristics. Survey data were successfully used to inform TG-275 recommendations.

Medical physics practice guideline 4.b: Development, implementation, use and maintenance of safety checklists.

The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8000 members and is the principal organization of medical physicists in the US. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the US. Existing medical physics practice guidelines will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized. The following terms are used in the AAPM practice guidelines: Must and must not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline. While must is the term to be used in the guidelines, if an entity that adopts the guideline has shall as the preferred term, the AAPM considers that must and shall have the same meaning. Should and should not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances.

Brain FNDC5/Irisin Expression in Patients and Mouse Models of Major Depression.

Major depressive disorder (MDD) is a major cause of disability in adults. MDD is both a comorbidity and a risk factor for Alzheimer's disease (AD), and regular physical exercise has been associated with reduced incidence and severity of MDD and AD. Irisin is an exercise-induced myokine derived from proteolytic processing of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5/irisin is reduced in the brains of AD patients and mouse models. However, whether brain FNDC5/irisin expression is altered in depression remains elusive. Here, we investigate changes in fndc5 expression in postmortem brain tissue from MDD individuals and mouse models of depression. We found decreased fndc5 expression in the MDD prefrontal cortex, both with and without psychotic traits. We further demonstrate that the induction of depressive-like behavior in male mice by lipopolysaccharide decreased fndc5 expression in the frontal cortex, but not in the hippocampus. Conversely, chronic corticosterone administration increased fndc5 expression in the frontal cortex, but not in the hippocampus. Social isolation in mice did not result in altered fndc5 expression in either frontal cortex or hippocampus. Finally, fluoxetine, but not other antidepressants, increased fndc5 gene expression in the mouse frontal cortex. Results indicate a region-specific modulation of fndc5 in depressive-like behavior and by antidepressant in mice. Our finding of decreased prefrontal cortex fndc5 expression in MDD individuals differs from results in mice, highlighting the importance of carefully interpreting observations in mice. The reduction in fndc5 mRNA suggests that decreased central FNDC5/irisin could comprise a shared pathologic mechanism between MDD and AD.

Assessment of dose-volume histogram precision for five clinical systems.

PURPOSE: To investigate the dependency of dose-volume histogram (DVH) behavior and precision on underlying discretization using shapes and dose distributions with known analytical DVHs for five commercial DVH calculators. METHODS: DVHs and summary metrics were extracted from all five systems using synthetic cone and cylinder objects for which the true volume and DVH curves were known. Trends in the curves and metrics were explored by varying the underlying voxelization of the CT image, structure set, and dose grid as well by varying the geometry of the structure and direction of a linear dose gradient. Using synthetic structures allowed for comparison with ground truth DVH curves to assess their accuracy while an algorithm was additionally developed to assess the precision of each system. The precision was calculated with a novel algorithm that treats any "stair step" behavior in a DVH curve as an uncertainty band and calculates the width, characterized as a percent difference, of the band for various DVH metrics. The underlying voxelization was additionally changed and DVHs were extracted for two clinical examples. The details of how each system calculated DVHs were also investigated and tendencies in the calculated curves, metrics, and precision were related to choices made in the calculation methodology. RESULTS: Calculation methodology differences that had a noticeable impact on the DVH curves and summary metrics include supersampling beyond the input grids and interpretation of the superior and inferior ends of the structures. Among the systems studied, the median precision ranged from 0.902% to 3.22%, and interquartile ranges varied from 1.09% to 3.91%. CONCLUSIONS: Commercial dose-evaluation solutions can calculate different DVH curves, structure volume measures, and dose statistics for the same input data due to differences in their calculation methodologies. This study highlights the importance of understanding and investigating the DVH calculation when considering a new clinical system and when using more than one system for data transfer.

Electronic charting of radiation therapy planning and treatment: Report of Task Group 262.

While most Radiation Oncology clinics have adopted electronic charting in one form or another, no consensus document exists that provides guidelines for safe and effective use of the Radiation Oncology electronic medical records (RO-EMR). Task Group 262 was formed to provide these guidelines as well as to provide recommendations to vendors for improving electronic charting functionality in future. Guidelines are provided in the following areas: Implementation and training for the RO-EMR, acceptance testing and quality assurance (QA) of the RO-EMR, use of the RO-EMR as an information repository, use of the RO-EMR as a workflow manager, electronic charting for brachytherapy and nonstandard treatments, and information technology (IT) considerations associated with the RO-EMR. The report was based on a literature search by the task group, an extensive survey of task group members on their respective RO-EMR practices, an AAPM membership survey on electronic charting, as well as group consensus.

Cerebrospinal Fluid Neurotransmitters, Cytokines, and Chemokines in Alzheimer's and Lewy Body Diseases.

BACKGROUND: Alzheimer's disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission. OBJECTIVE: We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients. METHODS: We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC). RESULTS: Among neurotransmitters, noradrenaline (NA) was increased in AD CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC. CONCLUSIONS: CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts.

Phantom Verification of AAA and Acuros Dose Calculations for Lung Cancer: Do Tumor Size and Regression Matter?

PURPOSE: This study aimed to evaluate dose calculation accuracy for the Eclipse Analytical Anisotropic Algorithm (AAA) and Acuros XB algorithm for various lung tumor sizes and to investigate dosimetric changes associated with treatment of regressing tumors. METHODS AND MATERIALS: A water phantom with cylindrical cork inserts (lung surrogates) was fabricated. Large (202 cm3), medium (54 cm3), and small (3 cm3) solid water tumors were implanted within cork inserts. A plain cork insert was used to simulate a lung without a tumor. The cork inserts and tumors were cut along the long axis, and Gafchromic film was placed between the sections to measure dose distributions. Three-dimensional conformal plans were created using 6 MV and 10 MV beams, and volumetric modulated arc therapy plans were created using 6 MV beams for each tumor size. Doses were calculated using Eclipse AAA and Acuros XB. The measured and calculated dose distributions were compared for each tumor size and treatment algorithm. To simulate a regressing tumor, the original plans created for the large tumor were separately delivered to the phantom that contained a small, medium, or no tumor. The dosimetric effects were evaluated using gamma passing rates with a 2%/2 mm criterion and dose profile comparisons. RESULTS: Agreement between the measurements and AAA calculations decreased as tumor size decreased, but Acuros XB showed better agreement for all tumor sizes. The largest difference was observed for a 6 MV volumetric modulated arc therapy plan created to treat the smallest tumor. The gamma passing rate was 89.7% but that of Acuros was 99.5%. For the tumor regression evaluation, the gamma passing rates ranged from 53% to 99% for AAA. For Acuros XB, the gamma passing rates were >98% for all scenarios. CONCLUSION: Both AAA and Acuros XB calculated the dose accurately for the largest lung tumor. For the smallest and regressing tumors, Acuros XB more accurately modelled the dose distribution compared with AAA.

Free-floating adult human brain-derived slice cultures as a model to study the neuronal impact of Alzheimer's disease-associated Aß oligomers.

BACKGROUND: Slice cultures have been prepared from several organs. With respect to the brain, advantages of slice cultures over dissociated cell cultures include maintenance of the cytoarchitecture and neuronal connectivity. Slice cultures from adult human brain have been reported and constitute a promising method to study neurological diseases. Despite this potential, few studies have characterized in detail cell survival and function along time in short-term, free-floating cultures. NEW METHOD: We used tissue from adult human brain cortex from patients undergoing temporal lobectomy to prepare 200 µm-thick slices. Along the period in culture, we evaluated neuronal survival, histological modifications, and neurotransmitter release. The toxicity of Alzheimer's-associated Aß oligomers (AßOs) to cultured slices was also analyzed. RESULTS: Neurons in human brain slices remain viable and neurochemically active for at least four days in vitro, which allowed detection of binding of AßOs. We further found that slices exposed to AßOs presented elevated levels of hyperphosphorylated Tau, a hallmark of Alzheimer's disease. COMPARISON WITH EXISTING METHOD(S): Although slice cultures from adult human brain have been previously prepared, this is the first report to analyze cell viability and neuronal activity in short-term free-floating cultures as a function of days in vitro. CONCLUSIONS: Once surgical tissue is available, the current protocol is easy to perform and produces functional slices from adult human brain. These slice cultures may represent a preferred model for translational studies of neurodegenerative disorders when long term culturing in not required, as in investigations on AßO neurotoxicity.

Design and clinical use of a rotational phantom for dosimetric verification of IMRT/VMAT treatments.

PURPOSE: To describe the design and clinical use of a rotational phantom for dosimetric verification of IMRT/VMAT treatment plans using radiochromic film. METHODS: A solid water cylindrical phantom was designed with separable upper and lower halves and rests on plastic bearings allowing for 360° rotation about its central axis. The phantom accommodates a half sheet of radiochromic film, and by rotating the cylinder, the film can be placed in any plane between coronal and sagittal. Calculated dose planes coinciding with rotated film measurements are exported by rotating the CT image and dose distribution within the treatment planning system. The process is illustrated with 2 rotated film measurements of an SRS treatment plan involving 4 separate targets. Additionally, 276 patient specific QA measurements were obtained with the phantom and analyzed with a 2%/2 mm gamma criterion. RESULTS: The average 2%/2 mm gamma passing rate for all 276 plans was 99.3%. Seventy-two of the 276 plans were measured with the plane of the film rotated between the coronal and sagittal planes and had an average passing rate of 99.4%. CONCLUSIONS: The rotational phantom allows for accurate film measurements in any plane. With this technique, regions of a dose distribution which might otherwise require multiple sagittal or coronal measurements can be verified with as few as a single measurement. This increases efficiency and, in combination with the high spatial resolution inherent to film dosimetry, makes the rotational technique an attractive option for patient-specific QA.

Image-guided radiotherapy quality control: Statistical process control using image similarity metrics.

PURPOSE: The purpose of this study was to demonstrate an objective quality control framework for the image review process. METHODS AND MATERIALS: A total of 927 cone-beam computed tomography (CBCT) registrations were retrospectively analyzed for 33 bilateral head and neck cancer patients who received definitive radiotherapy. Two registration tracking volumes (RTVs) - cervical spine (C-spine) and mandible - were defined, within which a similarity metric was calculated and used as a registration quality tracking metric over the course of treatment. First, sensitivity to large misregistrations was analyzed for normalized cross-correlation (NCC) and mutual information (MI) in the context of statistical analysis. The distribution of metrics was obtained for displacements that varied according to a normal distribution with standard deviation of σ = 2 mm, and the detectability of displacements greater than 5 mm was investigated. Then, similarity metric control charts were created using a statistical process control (SPC) framework to objectively monitor the image registration and review process. Patient-specific control charts were created using NCC values from the first five fractions to set a patient-specific process capability limit. Population control charts were created using the average of the first five NCC values for all patients in the study. For each patient, the similarity metrics were calculated as a function of unidirectional translation, referred to as the effective displacement. Patient-specific action limits corresponding to 5 mm effective displacements were defined. Furthermore, effective displacements of the ten registrations with the lowest similarity metrics were compared with a three dimensional (3DoF) couch displacement required to align the anatomical landmarks. RESULTS: Normalized cross-correlation identified suboptimal registrations more effectively than MI within the framework of SPC. Deviations greater than 5 mm were detected at 2.8σ and 2.1σ from the mean for NCC and MI, respectively. Patient-specific control charts using NCC evaluated daily variation and identified statistically significant deviations. This study also showed that subjective evaluations of the images were not always consistent. Population control charts identified a patient whose tracking metrics were significantly lower than those of other patients. The patient-specific action limits identified registrations that warranted immediate evaluation by an expert. When effective displacements in the anterior-posterior direction were compared to 3DoF couch displacements, the agreement was ±1 mm for seven of 10 patients for both C-spine and mandible RTVs. CONCLUSIONS: Qualitative review alone of IGRT images can result in inconsistent feedback to the IGRT process. Registration tracking using NCC objectively identifies statistically significant deviations. When used in conjunction with the current image review process, this tool can assist in improving the safety and consistency of the IGRT process.

Crosstalk between endoplasmic reticulum stress and brain inflammation in Alzheimer's disease.

While most often noted for its cognitive symptoms, Alzheimer's disease (AD) is, at its core, a disease of protein misfolding/aggregation, with an intriguing inflammatory component. Defective clearance and/or abnormal production of the amyloid-ß peptide (Aß), and its ensuing accumulation and aggregation, underlie two hallmark features of AD: brain accumulation of insoluble protein deposits known as amyloid or senile plaques, and buildup of soluble Aß oligomers (AßOs), diffusible toxins linked to synapse dysfunction and memory impairment. In neurons, as in typical eukaryotic cells, the endoplasmic reticulum (ER) serves as a main compartment for the folding, maturation, trafficking and quality control of newly synthesized proteins. The ER lumen, a calcium-rich, oxidizing environment, provides favorable conditions for these physiological functions to occur. These conditions, however, also favor protein aggregation. Several stressors, including metabolic/nutrient stress and certain pathologies, may upset the ER homeostasis, e.g., by affecting calcium levels or by causing the accumulation of unfolded or misfolded proteins. Whatever the underlying cause, the result is what is commonly known as "ER stress". This, in turn, triggers a conserved cellular response mechanism known as the "unfolded protein response" (UPR). The UPR comprises three pathways involving transcriptional or translational regulators aimed at normalizing ER function, and each of them results in pro-inflammatory signaling. A positive feedback loop exists between ER stress and inflammation, with clear implications for neurodegeneration and AD. Here, we explore recent findings on the role of ER stress and the UPR in inflammatory processes leading to synapse failure and memory impairment in AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

Patient safety is improved with an incident learning system-Clinical evidence in brachytherapy.

BACKGROUND AND PURPOSE: Health leaders have advocated for incident learning systems (ILSs) to prevent errors, but there is limited evidence demonstrating that ILSs improve cancer patient safety. Herein, we report a long-term retrospective review of ILS reports for the brachytherapy practice at a large academic institution. MATERIAL AND METHODS: Over a nine-year period, the brachytherapy practice was encouraged to report all standard operating procedure deviations, including low risk deviations. A multidisciplinary committee assigned root causes and risk scores to all incidents. Evidence based practice changes were made using ILS data, and relevant incidents were communicated to all staff in order to reduce recurrence rates. RESULTS: 5258 brachytherapy procedures were performed and 2238 incidents were reported from 2007 to 2015. A ramp-up period was observed in ILS participation between 2007 (0.12 submissions/procedures) and 2011 (1.55 submissions/procedures). Participation remained stable between 2011 and 2015, and we achieved a 60% (p<0.001) decrease in the risk of dose error or violation of radiation safety policy and a 70% (p<0.001) decrease in frequency of high composite-risk scores. Significant decreases were also observed in incidents with root causes of poor communication (60% decrease, p<0.001) and poor quality of written procedures (59% decrease, p<0.001). CONCLUSIONS: Implementation of an ILS in brachytherapy significantly reduced risk during cancer patient care. Safety improvements have been sustained over several years.

Brain infusion of α-synuclein oligomers induces motor and non-motor Parkinson's disease-like symptoms in mice.

Parkinson's disease (PD) is characterized by motor dysfunction, which is preceded by a number of non-motor symptoms including olfactory deficits. Aggregation of α-synuclein (α-syn) gives rise to Lewy bodies in dopaminergic neurons and is thought to play a central role in PD pathology. However, whether amyloid fibrils or soluble oligomers of α-syn are the main neurotoxic species in PD remains controversial. Here, we performed a single intracerebroventricular (i.c.v.) infusion of α-syn oligomers (α-SYOs) in mice and evaluated motor and non-motor symptoms. Familiar bedding and vanillin essence discrimination tasks showed that α-SYOs impaired olfactory performance of mice, and decreased TH and dopamine levels in the olfactory bulb early after infusion. The olfactory deficit persisted until 45days post-infusion (dpi). α- SYO-infused mice behaved normally in the object recognition and forced swim tests, but showed increased anxiety-like behavior in the open field and elevated plus maze tests 20 dpi. Finally, administration of α-SYOs induced late motor impairment in the pole test and rotarod paradigms, along with reduced TH and dopamine content in the caudate putamen, 45 dpi. Reduced number of TH-positive cells was also seen in the substantia nigra of α-SYO-injected mice compared to control. In conclusion, i.c.v. infusion of α-SYOs recapitulated some of PD-associated non-motor symptoms, such as increased anxiety and olfactory dysfunction, but failed to recapitulate memory impairment and depressive-like behavior typical of the disease. Moreover, α-SYOs i.c.v. administration induced motor deficits and loss of TH and dopamine levels, key features of PD. Results point to α-syn oligomers as the proximal neurotoxins responsible for early non-motor and motor deficits in PD and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of PD novel therapeutic targets and drug screening.

Cross Talk Between Brain Innate Immunity and Serotonin Signaling Underlies Depressive-Like Behavior Induced by Alzheimer's Amyloid-ß Oligomers in Mice.

Considerable clinical and epidemiological evidence links Alzheimer's disease (AD) and depression. However, the molecular mechanisms underlying this connection are largely unknown. We reported recently that soluble Aß oligomers (AßOs), toxins that accumulate in AD brains and are thought to instigate synapse damage and memory loss, induce depressive-like behavior in mice. Here, we report that the mechanism underlying this action involves AßO-induced microglial activation, aberrant TNF-α signaling, and decreased brain serotonin levels. Inactivation or ablation of microglia blocked the increase in brain TNF-α and abolished depressive-like behavior induced by AßOs. Significantly, we identified serotonin as a negative regulator of microglial activation. Finally, AßOs failed to induce depressive-like behavior in Toll-like receptor 4-deficient mice and in mice harboring a nonfunctional TLR4 variant in myeloid cells. Results establish that AßOs trigger depressive-like behavior via a double impact on brain serotonin levels and microglial activation, unveiling a cross talk between brain innate immunity and serotonergic signaling as a key player in mood alterations in AD. SIGNIFICANCE STATEMENT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia in the world. Brain accumulation of amyloid-ß oligomers (AßOs) is a major feature in the pathogenesis of AD. Although clinical and epidemiological data suggest a strong connection between AD and depression, the underlying mechanisms linking these two disorders remain largely unknown. Here, we report that aberrant activation of the brain innate immunity and decreased serotonergic tonus in the brain are key players in AßO-induced depressive-like behavior in mice. Our findings may open up new possibilities for the development of effective therapeutics for AD and depression aimed at modulating microglial function.

Single exposure to cocaine impairs aspartate uptake in the pre-frontal cortex via dopamine D1-receptor dependent mechanisms.

Dopamine and glutamate play critical roles in the reinforcing effects of cocaine. We demonstrated that a single intraperitoneal administration of cocaine induces a significant decrease in [(3)H]-d-aspartate uptake in the pre-frontal cortex (PFC). This decrease is associated with elevated dopamine levels, and requires dopamine D1-receptor signaling (D1R) and adenylyl cyclase activation. The effect was observed within 10min of cocaine administration and lasted for up to 30min. This rapid response is related to D1R-mediated cAMP-mediated activation of PKA and phosphorylation of the excitatory amino acid transporters EAAT1, EAAT2 and EAAT3. We also demonstrated that cocaine exposure increases extracellular d-aspartate, l-glutamate and d-serine in the PFC. Our data suggest that cocaine activates dopamine D1 receptor signaling and PKA pathway to regulate EAATs function and extracellular EAA level in the PFC.

Cadaveric verification of the Eclipse AAA algorithm for spine SBRT treatments with titanium hardware.

PURPOSE: To assess the accuracy of the Eclipse Analytical Anisotropic Algorithm when calculating dose for spine stereotactic body radiation therapy treatments involving surgically implanted titanium hardware. METHODS AND MATERIALS: A human spine was removed from a cadaver, cut sagittally along the midline, and then separated into thoracic and lumbar sections. The thoracic section was implanted with titanium stabilization hardware; the lumbar section was not implanted. Spine sections were secured in a water phantom and simulated for treatment planning using both standard and extended computed tomography (CT) scales. Target volumes were created on both spine sections. Dose calculations were performed using (1) the standard CT scale with relative electron density (RED) override of image artifacts and hardware, (2) the extended CT scale with RED override of image artifacts only, and (3) the standard CT scale with no RED overrides for hardware or artifacts. Plans were delivered with volumetric modulated arc therapy using a 6-MV beam with and without a flattening filter. A total of 3 measurements for each plan were made with Gafchromic film placed between the spine sections and compared with Eclipse dose calculations using gamma analysis with a 2%/2 mm passing criteria. A single measurement in a homogeneous phantom was made for each plan before actual delivery. RESULTS: Gamma passing rates for measurements in the homogeneous phantom were 99.6% or greater. Passing rates for measurements made in the lumbar spine section without hardware were 99.3% or greater; measurements made in the thoracic spine containing titanium were 98.6 to 99.5%. CONCLUSIONS: Eclipse Analytical Anisotropic Algorithm can adequately model the effects of titanium implants for spine stereotactic body radiation therapy treatments using volumetric modulated arc therapy. Calculations with standard or extended CT scales give similarly accurate results.