Association between military service and Alzheimer's disease neuropathology at autopsy.

INTRODUCTION: Anti-amyloid therapies are at the forefront of efforts to treat Alzheimer's disease (AD). Identifying amyloid risk factors may aid screening and intervention strategies. While veterans face increased exposure to risk factors, whether they face a greater neuropathologic amyloid burden is not well understood. METHODS: Male decedents donating to two Alzheimer's Disease Research Center (ADRC) brain banks from 1986 to 2018 with categorized neuritic plaque density and neurofibrillary tangles (n = 597) were included. Using generalized ordered logistic regression we modeled each outcome's association with military history adjusting for age and death year. RESULTS: Having served in the military (60% of sample) is associated with post mortem neuritic amyloid plaque (for each comparison of higher to lower C scores OR = 1.26; 95% confidence interval [CI] = 1.06-1.49) and tau pathology (B score OR = 1.10; 95% CI = 1.08-1.12). DISCUSSION: This is the first study, to our knowledge, finding increased levels of verified AD neuropathology in those with military service. Targeted veteran AD therapies is a pressing need.

Brachial plexus anatomy in the miniature swine as compared to human.

Brachial plexus injury (BPI) occurs when the brachial plexus is compressed, stretched, or avulsed. Although rodents are commonly used to study BPI, these models poorly mimic human BPI due to the discrepancy in size. The objective of this study was to compare the brachial plexus between human and Wisconsin Miniature SwineTM (WMSTM ), which are approximately the weight of an average human (68-91 kg), to determine if swine would be a suitable model for studying BPI mechanisms and treatments. To analyze the gross anatomy, WMS brachial plexuses were dissected both anteriorly and posteriorly. For histological analysis, sections from various nerves of human and WMS brachial plexuses were fixed in 2.5% glutaraldehyde, and postfixed with 2% osmium tetroxide. Subsequently paraffin sections were counter-stained with Masson's Trichrome. Gross anatomy revealed that the separation into three trunks and three cords is significantly less developed in the swine than in human. In swine, it takes the form of upper, middle, and lower systems with ventral and dorsal components. Histological evaluation of selected nerves revealed differences in nerve trunk diameters and the number of myelinated axons in the two species. The WMS had significantly fewer myelinated axons than humans in median (p = 0.0049), ulnar (p = 0.0002), and musculocutaneous nerves (p = 0.0454). The higher number of myelinated axons in these nerves for humans is expected because there is a high demand of fine motor and sensory functions in the human hand. Due to the stronger shoulder girdle muscles in WMS, the WMS suprascapular and axillary nerves were larger than in human. Overall, the WMS brachial plexus is similar in size and origin to human making them a very good model to study BPI. Future studies analyzing the effects of BPI in WMS should be conducted.

Proteomic Atlas of the Human Brain in Alzheimer's Disease.

The brain represents one of the most divergent and critical organs in the human body. Yet, it can be afflicted by a variety of neurodegenerative diseases specifically linked to aging, about which we lack a full biomolecular understanding of onset and progression, such as Alzheimer's disease (AD). Here we provide a proteomic resource comprising nine anatomically distinct sections from three aged individuals, across a spectrum of disease progression, categorized by quantity of neurofibrillary tangles. Using state-of-the-art mass spectrometry, we identify a core brain proteome that exhibits only small variance in expression, accompanied by a group of proteins that are highly differentially expressed in individual sections and broader regions. AD affected tissue exhibited slightly elevated levels of tau protein with similar relative expression to factors associated with the AD pathology. Substantial differences were identified between previous proteomic studies of mature adult brains and our aged cohort. Our findings suggest considerable value in examining specifically the brain proteome of aged human populations from a multiregional perspective. This resource can serve as a guide, as well as a point of reference for how specific regions of the brain are affected by aging and neurodegeneration.

Neck Rhabdoid Tumors: Clinical Features and Consideration of Autologous Stem Cell Transplant.

Extrarenal malignant rhabdoid tumors (MRT) have a poor prognosis despite aggressive therapy. Adding high-dose chemotherapy with autologous stem cell rescue (HDC-ASCR) as consolidative therapy for MRT is controversial. We describe 2 patients, age 13 years and 19 months, with unresectable neck MRT. After chemotherapy and radiotherapy, both underwent HDC-ASCR and remain in remission over 4 years later. We reviewed all published cases of neck MRT, and found poorer outcomes and more variable age of presentation and time to progression than MRT at other sites. Neck MRT may represent a higher-risk subset of MRT, and addition of HDC-ASCR merits consideration.

Neurofibromatosis type 1: A neuro-psycho-cutaneous syndrome?

Neurofibromatosis type 1 (NF1) is an inherited disorder often associated with optic nerve gliomas, low-grade brain tumors, and readily visible signs. Though these features are frequently emphasized, the psychosocial and emotional morbidities are often overlooked. We present a patient with depressive disorder resulting in suicide in a patient with NF1.

Actionable diagnosis of neuroleptospirosis by next-generation sequencing.

A 14-year-old boy with severe combined immunodeficiency presented three times to a medical facility over a period of 4 months with fever and headache that progressed to hydrocephalus and status epilepticus necessitating a medically induced coma. Diagnostic workup including brain biopsy was unrevealing. Unbiased next-generation sequencing of the cerebrospinal fluid identified 475 of 3,063,784 sequence reads (0.016%) corresponding to leptospira infection. Clinical assays for leptospirosis were negative. Targeted antimicrobial agents were administered, and the patient was discharged home 32 days later with a status close to his premorbid condition. Polymerase-chain-reaction (PCR) and serologic testing at the Centers for Disease Control and Prevention (CDC) subsequently confirmed evidence of Leptospira santarosai infection.

The sulci of the inferior surface of the temporal lobe: An anatomical study.

Understanding the anatomy of temporal lobe sulci and their variations can allow for safer neurosurgical approaches. Although the inferior temporal sulci and their relations to each other has been described by several authors, the nomenclature used has not been universal. The aim of this study was to investigate the anatomic features of the three main sulci of the inferior temporal lobe and provide a simple description of complex patterns among these sulci. Sulcal variations and their relations were examined in seventy formalin-fixed, adult cadaveric cerebral hemispheres. We recommend a simple but modified classification specifically for anatomic variations of the rhinal and collateral sulci. Furthermore, we describe the frequency of occipitotemporal sulci that contain 5 and 6 segments, not previously mentioned. The length and depth of all sulci were measured in all samples. Additionally, more detailed results regarding the patterns, courses, connections, relationships and measurements were given. Understanding of the complex anatomy of this clinically important region is of benefit to neurosurgeons, providing necessary guidance for neurosurgical approaches to the inferior surface of the temporal lobe. Clin. Anat. 29:932-942, 2016. © 2016 Wiley Periodicals, Inc.

Microsurgical anatomy of the posterior median septum of the human spinal cord.

The aim of this study was to analyze the topographical anatomy of the dorsal spinal cord (SC) in relation to the posterior median septum (PMS). This included the course and variations in the PMS, and its relationship to and distance from other dorsal spinal landmarks. Microsurgical anatomy of the PMS was examined in 12 formalin-fixed adult cadaveric SCs. Surface landmarks such as the dorsal root entry zone (DREZ), the denticulate ligament, the architecture of the leptomeninges and pial vascular distribution were noted. The PMS was examined histologically in all spinal segments. The PMS extended most deeply at spinal segments C7 and S4. This was statistically significant for all spinal segments except C5. The PMS was shallowest at segments T4 and T6, where it was statistically significantly thinner than at any other segment. In 80% of the SCs, small blood vessels were identified that traveled in a rostrocaudal direction in the PMS. The longest distance between the PMS and the DREZ was at the C1-C4 vertebral levels and the shortest distance was at the S5 level. Prevention of deficits following a dorsal midline neurosurgical approach to deep-seated SC lesions requires careful identification of the midline of the cord. The PMS and septum define the midline on the dorsum of the SC and their accurate identification is essential for a safe midline surgical approach. In this anatomical study, we describe the surface anatomy of the dorsal SC and its relationship with the PMS, which can be used to determine a safe entry zone into the SC.

FABP7 drives an inflammatory response in human astrocytes and is upregulated in Alzheimer's disease.

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is characterized by the accumulation of intracellular neurofibrillary tangles, extracellular amyloid plaques, and neuroinflammation. In partnership with microglial cells, astrocytes are key players in the regulation of neuroinflammation. Fatty acid binding protein 7 (FABP7) belongs to a family of conserved proteins that regulate lipid metabolism, energy homeostasis, and inflammation. FABP7 expression is largely restricted to astrocytes and radial glia-like cells in the adult central nervous system. We observed that treatment of primary hippocampal astrocyte cultures with amyloid ß fragment 25-35 (Aß25-35) induces FABP7 upregulation. In addition, FABP7 expression is upregulated in the brain of APP/PS1 mice, a widely used AD mouse model. Co-immunostaining with specific astrocyte markers revealed increased FABP7 expression in astrocytes. Moreover, astrocytes surrounding amyloid plaques displayed increased FABP7 staining when compared to non-plaque-associated astrocytes. A similar result was obtained in the brain of AD patients. Whole transcriptome RNA sequencing analysis of human astrocytes differentiated from induced pluripotent stem cells (i-astrocytes) overexpressing FABP7 identified 500 transcripts with at least a 2-fold change in expression. Gene Ontology enrichment analysis identified (i) positive regulation of cytokine production and (ii) inflammatory response as the top two statistically significant overrepresented biological processes. We confirmed that wild-type FABP7 overexpression induces an NF-κB-driven inflammatory response in human i-astrocytes. On the other hand, the expression of a ligand-binding impaired mutant FABP7 did not induce NF-κB activation. Together, our results suggest that the upregulation of FABP7 in astrocytes could contribute to the neuroinflammation observed in AD.

Pathologic classification of a late-onset peripheral neuropathy in a spontaneous Labrador retriever dog model.

Late-onset peripheral neuropathy (LPN) is a heritable canine neuropathy commonly found in Labrador retrievers and is characterized by laryngeal paralysis and pelvic limb paresis. Our objective was to establish canine LPN as a model for human hereditary peripheral neuropathy by classifying it as either an axonopathy or myelinopathy and evaluating length-dependent degeneration. We conducted a motor nerve conduction study of the sciatic and ulnar nerves, electromyography (EMG) of appendicular and epaxial musculature, and histologic analysis of sciatic and recurrent laryngeal nerves in LPN-affected and control dogs. LPN-affected dogs exhibited significant decreases in compound muscle action potential (CMAP) amplitude, CMAP area, and pelvic limb latencies. However, no differences were found in motor nerve conduction velocity, residual latencies, or CMAP duration. Distal limb musculature showed greater EMG changes in LPN-affected dogs. Histologically, LPN-affected dogs exhibited a reduction in the number of large-diameter axons, especially in distal nerve regions. In conclusion, LPN in Labrador retrievers is a common, spontaneous, length-dependent peripheral axonopathy that is a novel animal model of age-related peripheral neuropathy that could be used for fundamental research and clinical trials.

Biochemical inhibition of the acetyltransferases ATase1 and ATase2 reduces ß-secretase (BACE1) levels and Aß generation.

The cellular levels of ß-site APP cleaving enzyme 1 (BACE1), the rate-limiting enzyme for the generation of the Alzheimer disease (AD) amyloid ß-peptide (Aß), are tightly regulated by two ER-based acetyl-CoA:lysine acetyltransferases, ATase1 and ATase2. Here we report that both acetyltransferases are expressed in neurons and glial cells, and are up-regulated in the brain of AD patients. We also report the identification of first and second generation compounds that inhibit ATase1/ATase2 and down-regulate the expression levels as well as activity of BACE1. The mechanism of action involves competitive and non-competitive inhibition as well as generation of unstable intermediates of the ATases that undergo degradation.

Oncogenic Kras expression in postmitotic neurons leads to S100A8-S100A9 protein overexpression and gliosis.

Previous studies suggest that up-regulation of Ras signaling in neurons promotes gliosis and astrocytoma formation in a cell nonautonomous manner. However, the underlying mechanisms remain unknown. To address this question, we generated compound mice (LSL Kras G12D/+;CamKII-Cre) that express oncogenic Kras from its endogenous locus in postmitotic neurons after birth. These mice developed progressive gliosis, which is associated with hyperactivation of Ras signaling pathways. Microarray analysis identified S100A8 and S100A9 as two secreted molecules that are significantly overexpressed in mutant cortices. In contrast to their usual predominant expression in myeloid cells, we found that overexpression of S100A8 and S100A9 in the mutant cortex is primarily in neurons. This neuronal expression pattern is associated with increased infiltration of microglia in mutant cortex. Moreover, purified S100A8-S100A9 but not S100A8 or S100A9 alone promotes growth of primary astrocytes in vitro through both TLR4 and receptor of advanced glycation end product receptors. In summary, our results identify overexpression of S100A8-S100A9 in neurons as an early step in oncogenic Kras-induced gliosis. These molecules expressed in nonhematopoietic cells may be involved in tumorigenesis at a stage much earlier than what has been reported previously.

The subparietal and parietooccipital sulci: an anatomical study.

The subparietal and parietooccipital sulci are both located on the medial surface of the brain. Both of these sulci reveal significant variability in pattern and complexity. Both subparietal and parietooccipital sulci play an important role as surgical landmarks using posterior interhemispheric parietooccipital approach to lesions located adjacent to the ventricular trigon deep to the cingulate gyrus. The aim of this study is to analyze variations in the patterns of the subparietal and parietooccipital sulci and to emphasize their surgical importance. Fifty-six formalin-fixed cadaveric cerebral hemispheres from 28 adult humans are examined. Subparietal and parietal sulci patterns, variations and their relationship with the cingulate sulcus are studied according to the terminology introduced by Ono et al. The H-pattern was observed in 50% (n = 28) of all hemispheres, being the most common pattern of the subparietal sulcus. The Straight pattern was observed in the 30.4% (n = 17) of all hemispheres, being the most common pattern of the parietooccipital sulcus. Furthermore, more detailed results among the patterns, connections, side branches and the relationship with the adjacent sulci are given. Our study further confirms the complexities in the patterns of the subparietal and parietooccipital sulci and demonstrates that these sulci fall within an expected range of variations. Better knowledge of these variations will further help neurosurgeons to navigate easily during approaches involving the medial surface of the parietal lobe. Clin. Anat. 26:667-674, 2013. © 2013 Wiley Periodicals, Inc.

A Rare Case of Precocious Puberty Secondary to an LH-secreting Pituitary Adenoma.

An 8-year, 7-month-old male presented with puberty symptoms, including a 1.5-year history of facial hair with 9 months of phallic growth, body odor, and acne. Physical examination revealed phallic enlargement but only 4 mL testes bilaterally. Laboratory evaluation revealed markedly elevated LH and testosterone, but a prepubertal FSH level and minimally elevated adrenal androgens. A magnetic resonance imaging scan of the head revealed an anterior pituitary adenoma, and after the patient failed to respond to leuprolide, he was initiated on spironolactone and anastrozole to minimize pubertal progression before transsphenoidal adenomectomy. Postoperatively, the patient had rapid reduction of LH and testosterone, with subsequent cessation of pubertal progression, confirming the diagnosis of an LH-secreting pituitary adenoma despite negative immunoreactivity for LH and FSH. Functioning gonadotroph adenomas are rare and have been documented only in small case series and case reports. When active, these most commonly secrete FSH or co-secrete FSH and LH, and only very rarely result in precocious puberty. Here, we describe a rare case of an isolated LH-secreting functioning gonadotroph adenoma resulting in precocious puberty. This case reinforces the need to critically analyze departures from the typical pubertal sequence and to expand one's differential to include etiologies that can cause unbalanced secretion of gonadotropins.

Organ weight changes associated with body mass index determined from a medical autopsy population.

CONTEXT: Existing organ weight charts used by pathologists for patients undergoing medical autopsy do not illustrate the effect of obesity and age on organ weights among a general population of older individuals with multiple comorbidities. METHODS: We retrospectively reviewed 300 medical autopsy reports to extract data to analyze the effect of obesity and age on organ weights. RESULTS: In both men and women, there were statistically significant increases in organ weights with body mass index (BMI) but decreases with age for liver, spleen, and kidneys. In men, increased age was associated with increased left ventricular wall thickness, whereas increased BMI was associated with increased heart weight. In women, only BMI was associated with changes in all 3 anatomic cardiac parameters (heart weight and thickness of the right and left ventricular walls). Age effects were not observed for heart parameters in women. Thyroid weight increased with BMI in men but not in women. CONCLUSIONS: The findings demonstrate changes in organ weights/sizes with obesity and age in a population of patients with multiple comorbidities. The differential effects of age and BMI on the heart between men and women raise the possibility that increased BMI in women may have a greater impact on cardiovascular causes of death than that in men.

Malignant Transformation of Recurrent Residual Cerebellopontine Angle Epidermoid Tumor: Significance of Clinical Vigilance and Long-Term Surveillance.

Epidermoid tumors (ET) are slow-growing masses where malignant transformations occur extremely rarely. Malignant transformation warning signs are the rapid-onset, progression, and recurrence of symptoms. The radiologic evidence for malignant transformation is contrast enhancement with rapid growth, observed with magnetic resonance imaging (MRI) or computed tomography scans. Here, we provide a case report of a 68-year-old woman with a long-standing history of left-sided cerebellopontine angle ET who presented with a recent worsening of symptoms, and MRI observation of new ET contrast enhancement. Surgical re-exploration and histopathologic confirmation are mandatory in this setting of recent symptom worsening and MRI observation of rapid mass growth.

Distraction osteogenesis-induced muscle fibrosis may not be associated with TGF-ß1.

BACKGROUND: Transforming growth factor-ß 1 (TGF-ß1) participates in the synthesis and deposition of collagen. It has been implicated in fibrosis of tendons in wound-healing models but has never been studied in muscles with respect to distraction osteogenesis. METHODS: Using a rabbit model of distraction osteogenesis, we distracted the left tibias of 36 New Zealand white rabbits at 0.75 mm/d for 20 days. To determine whether suramin, an antagonist of TGF-ß, could aid in the prevention of fibrosis, we injected it into the anterior tibialis muscle [12 rabbits received low-dose suramin (50 mg), 12 received high-dose suramin (100 mg), and 12 received sham injections]. Half of each group was killed at the end of distraction (day 24) and the other half at day 60. At the time of killing the rabbits, joint range of motion was measured, and strength and morphometric measures of the muscle were taken. Muscle was harvested and immunolabeled for TGF-ß1. All findings were compared between study limbs and control (right) limbs. RESULTS: The comparison failed to demonstrate improvements in the range of motion, and in strength or morphometric muscle development. Immunolabeling for TGF-ß1 failed to show any staining in the intramuscular fibrosis. Paradoxically, muscle injected with high-dose suramin had the highest degree of fibrosis. CONCLUSIONS: We conclude that TGF-ß1 may not be the primary mediator of muscle fibrosis in distraction osteogenesis. CLINICAL RELEVANCE: Injection of suramin may not prevent contracture formation after distraction osteogenesis.

MR1 overexpression correlates with poor clinical prognosis in glioma patients.

BACKGROUND: Glioblastoma is the most common adult primary brain tumor with near-universal fatality. Major histocompatibility complex (MHC) class I molecules are important mediators of CD8 activation and can be downregulated by cancer cells to escape immune surveillance. MR1 is a nonclassical MHC-I-like molecule responsible for the activation of a subset of T cells. Although high levels of MR1 expression should enhance cancer cell recognition, various tumors demonstrate MR1 overexpression with unknown implications. Here, we study the role of MR1 in glioma. METHODS: Using multi-omics data from the Cancer Genome Atlas (TCGA), we studied MR1 expression patterns and its impact on survival for various solid tumors. In glioma specifically, we validated MR1 expression by histology, elucidate transcriptomic profiles of MR1 high versus low gliomas. To understand MR1 expression, we analyzed the methylation status of the MR1 gene and MR1 gene-related transcription factor (TF) expression. RESULTS: MR1 is overexpressed in all grades of glioma and many other solid cancers. However, only in glioma, MR1 overexpression correlated with poor overall survival and demonstrated global dysregulation of many immune-related genes in an MR1-dependent manner. MR1 overexpression correlated with decreased MR1 gene methylation and upregulation of predicted MR1 promoter binding TFs, implying MR1 gene methylation might regulate MR1 expression in glioma. CONCLUSIONS: Our in silico analysis shows that MR1 expression is a predictor of clinical outcome in glioma patients and is potentially regulated at the epigenetic level, resulting in immune-related genes dysregulation. These findings need to be validated using independent in vitro and in vivo functional studies.

Rhesus monkeys as a translational model for late-onset Alzheimer's disease.

Age is a major risk factor for late-onset Alzheimer's disease (AD) but seldom features in laboratory models of the disease. Furthermore, heterogeneity in size and density of AD plaques observed in individuals are not recapitulated in transgenic mouse models, presenting an incomplete picture. We show that the amyloid plaque microenvironment is not equivalent between rodent and primate species, and that differences in the impact of AD pathology on local metabolism and inflammation might explain established differences in neurodegeneration and functional decline. Using brain tissue from transgenic APP/PSEN1 mice, rhesus monkeys with age-related amyloid plaques, and human subjects with confirmed AD, we report altered energetics in the plaque microenvironment. Metabolic features included changes in mitochondrial distribution and enzymatic activity, and changes in redox cofactors NAD(P)H that were shared among species. A greater burden of lipofuscin was detected in the brains from monkeys and humans of advanced age compared to transgenic mice. Local inflammatory signatures indexed by astrogliosis and microglial activation were detected in each species; however, the inflamed zone was considerably larger for monkeys and humans. These data demonstrate the advantage of nonhuman primates in modeling the plaque microenvironment, and provide a new framework to investigate how AD pathology might contribute to functional loss.