Acute Infectious Proctitis in Adolescents.

The diagnosis of acute proctitis requires understanding who is at risk, being aware of symptoms, and leveraging a thorough sexual history with appropriate risk stratification to make the diagnosis. Cases have been concentrated in adolescents (ages 15-19 years), young adults (ages 20-24 years), men and transgender women who have sex with men, and those with a history of human immunodeficiency virus infection. Black adolescents experience a disproportionately high number of cases of proctitis due to an intersection of concentrated cases in sexual networks and delayed screening/diagnosis due to health care access barriers. Signs and symptoms include purulent discharge, bleeding, pain, tenesmus, pruritus, diarrhea or constipation, weight loss, or fever. Multisite sexually transmitted infection testing should be offered based on risk stratification (eg, history of condomless anal sex, oral intercourse, number of sex partners). Further management includes promotion of barrier protection and preexposure prophylaxis, routine surveillance, partner notification, and routine access to preventive immunizations.

Extracellular-Vesicle-Based Cancer Panels Diagnose Glioblastomas with High Sensitivity and Specificity.

Glioblastoma is one of the most devastating neoplasms of the central nervous system. This study focused on the development of serum extracellular vesicle (EV)-based glioblastoma tumor marker panels that can be used in a clinic to diagnose glioblastomas and to monitor tumor burden, progression, and regression in response to treatment. RNA sequencing studies were performed using RNA isolated from serum EVs from both patients (n = 85) and control donors (n = 31). RNA sequencing results for preoperative glioblastoma EVs compared to control EVs revealed 569 differentially expressed genes (DEGs, 2XFC, FDR < 0.05). By using these DEGs, we developed serum-EV-based biomarker panels for the following glioblastomas: wild-type IDH1 (96% sensitivity/80% specificity), MGMT promoter methylation (91% sensitivity/73% specificity), p53 gene mutation (100% sensitivity/89% specificity), and TERT promoter mutation (89% sensitivity/100% specificity). This is the first study showing that serum-EV-based biomarker panels can be used to diagnose glioblastomas with a high sensitivity and specificity.

Influence of MMR, MGMT Promotor Methylation and Protein Expression on Overall and Progression-Free Survival in Primary Glioblastoma Patients Treated with Temozolomide.

Glioblastoma is the most common malignant brain tumor in adults. Standard treatment includes tumor resection, radio-chemotherapy and adjuvant chemotherapy with temozolomide (TMZ). TMZ methylates DNA, whereas O6-methylguanine DNA methyltransferase (MGMT) counteracts TMZ effects by removing the intended proteasomal degradation signal. Non-functional MGMT mediates the mismatch repair (MMR) system, leading to apoptosis after futile repair attempts. This study investigated the associations between MGMT promoter methylation, MGMT and MMR protein expression, and their effect on overall survival (OS) and progression-free survival (PFS) in patients with glioblastoma. MGMT promoter methylation was assessed in 42 treatment-naïve patients with glioblastoma WHO grade IV by pyrosequencing. MGMT and MMR protein expression was analyzed using immunohistochemistry. MGMT promoter methylation was present in 52%, whereas patients <70 years of age revealed a significantly longer OS using a log-rank test and a significance threshold of p ≤ 0.05. MGMT protein expression and methylation status showed no correlation. MMR protein expression was present in all patients independent of MGMT status and did not influence OS and PFS. Overall, MGMT promoter methylation implicates an improved OS in patients with glioblastoma aged <70 years. In the elderly, the extent of surgery has an impact on OS rather than the MGMT promoter methylation or protein expression.

Opioid Legislation in Patients With Inflammatory Bowel Disease: A State-wide Retrospective Cohort Study.

BACKGROUND: Indiana State opioid prescription legislation has been shown to decrease overall opioid prescriptions. However, this effect has not been studied in specific diseases associated with chronic pain such as inflammatory bowel disease (IBD). We aimed to determine the effect of state opioid prescription legislation on opioid prescribing patterns in IBD. METHODS: A retrospective cohort analysis using an interrupted time-series from December 15, 2010 to July 1, 2018, with 2 time periods separated by Title 844 of the Indiana Administrative Code, in a statewide health care system capturing the majority of the state's population including all adult patients with IBD. The primary outcome was opioid prescription rate per person-year. RESULTS: In total, 9436 patients met inclusion criteria. After legislation, the total number of opioid orders per patient-year continued to increase (0.543, 95% CI, 0.528-0.558, to 0.663, 95% CI, 0.654-0.672), with fewer scripts from the emergency department (0.113, 95% CI, 0.106-0.120, to 0.092, 95% CI, 0.088-0.095) and more from outpatient providers (0.303, 95% CI, 0.292-0.314 to 0.432, 95% CI, 0.424-0.439). There were increases in biologic (0.206, 95% CI, 0.197-0.215 to 0.517, 95% CI, 0.509-0.525) and steroid (0.182, 95% CI, 0.173-0.190 to 0.237, 95% CI, 0.232-0.243) prescriptions per person-year following legislation. Factors associated with heavy opioid use included chronic steroids (odds ratio, 5.030; 95% CI, 4.176-6.054), history of IBD-related surgery (odds ratio, 2.807; 95% CI, 2.367-3.323) and current smoking (odds ratio, 2.650; 95% CI, 2.223-3.158). CONCLUSIONS: Despite legislation and the increased use of disease-modifying drugs, statewide opioid prescriptions continued to increase. The increase in opiate use, high steroid use, and significant health care utilization suggests poor underlying disease control.

State legislation, which has decreased opioid prescribing in the general population, has not had similar effects in patients with inflammatory bowel disease. This is the first study assessing opioid legislation and its effects in a chronic pain condition.

SRPX Emerges as a Potential Tumor Marker in the Extracellular Vesicles of Glioblastoma.

Extracellular vesicles (EVs) may be used as a non-invasive screening platform to discover markers associated with early diagnosis, prognosis, and treatment response. Such an approach is invaluable for diseases such as glioblastoma, for which only a few non-invasive diagnostic or prognostic markers are available. We used mass spectrometry to analyze proteomics profiles of EVs derived from four glioblastoma cell lines and human primary astrocytes (HPAs) and found that SRPX is the only protein enriched in the majority of glioblastoma EVs that was absent in the HPA-derived EVs. Then, we evaluated the relationship between SRPX protein expression and tumor grade using immunohistochemical staining (IHC) and performed colony formation and viability assays to analyze the possible function of SRPX in glioblastoma. SRPX mRNA and protein expression were associated with tumor grade. Moreover, temozolomide (TMZ)-resistant tumor tissues showed highly positive SRPX staining, compared to all other tumor grades. Additionally, glioblastoma cells displayed enhanced SRPX gene expression when exposed to TMZ. Knockdown of SRPX gene expression via siRNA inhibited cell viability. Taken together, the results of this study suggest that SRPX can be used as a novel tumor marker for diagnostic and prognostic purposes and can also be a therapeutic target for glioblastomas.

Functional Medicine Approach to Patient Care Improves Sleep, Fatigue, and Quality of Life in Patients With Inflammatory Bowel Disease.

Background: A Functional Medicine program was developed at an inflammatory bowel disease (IBD) center with the goal of integrating strategies to address modifiable lifestyle factors and to complete a 6-week elimination diet under the direction of a trained Functional Medicine dietitian and Functional Medicine providers. Methods: From January 2019 to November 2019, patients with controlled, but persistent, symptoms from IBD were offered enrollment. Each of the 5 visits incorporated an educational session focused on nutrition followed by a session focusing on modifiable lifestyle factors. The patients were placed on a supervised 6-week elimination diet. At each visit, patients completed the SIBDQ (Short Inflammatory Bowel Disease Questionnaire), FSS (Fatigue Severity Scale), PSQI (The Pittsburgh Sleep Quality Index), and MSQ (Medical Symptoms Questionnaire). Statistical analysis was performed using the Wilcoxon matched pairs signed-rank test. Results: Nineteen patients enrolled (2 men: 1 ulcerative colitis [UC], 1 Crohn's disease [CD]; 17 women: 3 UC, 14 CD). 15 patients completed all modules. There was improvement in all patient-reported outcomes (PROs) (FSS, P < .001; PSQI, P < .001; SIBDQ, P < .001; MSQ, P < .001). Every patient who completed the last session demonstrated weight loss. Conclusions: The psychoemotional roots to immune disease states, particularly IBD, are complicated and often not addressed in traditional care. We are just beginning to understand the impact of nutrition, sleep, stress, movement, and relationships on IBD. In this cohort, utilizing Functional Medicine as an adjunct to traditional care resulted in improvement in all PROs.

Histotype-Dependent Oligodendroglial PrP Pathology in Sporadic CJD: A Frequent Feature of the M2C "Strain".

In sporadic Creutzfeldt-Jakob disease, molecular subtypes are neuropathologically well identified by the lesioning profile and the immunohistochemical PrPd deposition pattern in the grey matter (histotypes). While astrocytic PrP pathology has been reported in variant CJD and some less frequent histotypes (e.g., MV2K), oligodendroglial pathology has been rarely addressed. We assessed a series of sCJD cases with the aim to identify particular histotypes that could be more prone to harbor oligodendroglial PrPd. Particularly, the MM2C phenotype, in both its more "pure" and its mixed MM1+2C or MV2K+2C forms, showed more frequent oligodendroglial PrP pathology in the underlying white matter than the more common MM1/MV1 and VV2 histotypes, and was more abundant in patients with a longer disease duration. We concluded that the MM2C strain was particularly prone to accumulate PrPd in white matter oligodendrocytes.

Co-incidental C9orf72 expansion mutation-related frontotemporal lobar degeneration pathology and sporadic Creutzfeldt-Jakob disease.

BACKGROUND: The C9orf72 hexanucleotide expansion mutation is the most common cause of genetic frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and combined FTD-ALS. Its underlying neuropathology combines TDP-43 pathology and dipeptide repeat protein (DPR) deposits and may also associate with other neurodegeneration-associated protein aggregates. Herein we present a unique combination of C9orf72 mutation with sporadic Creutzfeldt-Jakob disease (CJD) in a 74-year-old patient with rapidly progressive dementia. METHODS: Detailed neuropathological examination including immunohistochemistry for several proteinopathies. Genetic analysis was conducted by repeat primed polymerase chain reaction (PCR). Furthermore, we analyzed additional C9orf72 mutation carriers for prion-protein (PrP) deposits in brain tissue and screened the cerebellar cortex of other CJD cases for p62/DPR neuronal inclusions to assess the frequency of combined pathologies. RESULTS: Postmortem brain examination of a patient with a rapidly progressive neurological deterioration of 8 months' duration confirmed the diagnosis of CJD. She harbored valine homozygosity at PRNP codon 129. In addition, a frontotemporal lobar degeneration (FTLD)-pattern with TDP-43 protein aggregates and p62+/C9RANT+ positive inclusions along with a high degree of Alzheimer-related pathology (A3B3C3) were identified. The suspected C9orf72 expansion mutation was confirmed by repeat-primed PCR. Screening of 13 C9orf72 cases showed no pathological PrP aggregates and screening of 100 CJD cases revealed no other C9orf72 expansion mutation carriers. CONCLUSION: A combination of a C9orf72 expansion mutation-related FTLD with sporadic CJD in the same patient is rare. While the rarity of both diseases makes this concurrence most likely to be coincidental, questions regarding a potential link between these two neurodegenerative pathologies deserve further studies.

IgA Nephropathy in the Setting of Anti-TNF-α Therapy for Inflammatory Bowel Disease.

Tumor necrosis factor-α (TNF-α)-inhibiting agents are a standard therapy for moderate-to-severe inflammatory bowel disease (IBD). IgA nephropathy in the setting of prolonged exposure to TNF-α inhibitors is a rare, clinically significant adverse event often overlooked by gastroenterologists but well documented in the rheumatologic literature. We present a case series of 3 patients with IBD on TNF-α inhibitors who developed biopsy-proven IgA nephropathy. Clinicians prescribing TNF-α inhibitors to patients with IBD need to be aware of this potential side effect. Therapies with alternative mechanisms of action should instead be considered.

Mitochondrial respiratory chain deficiency correlates with the severity of neuropathology in sporadic Creutzfeldt-Jakob disease.

Mitochondrial dysfunction has been implicated in multiple neurodegenerative diseases but remains largely unexplored in Creutzfeldt-Jakob disease. Here, we characterize the mitochondrial respiratory chain at the individual neuron level in the MM1 and VV2 common molecular subtypes of sporadic Creutzfeldt-Jakob disease. Moreover, we investigate the associations between the mitochondrial respiratory chain and neuropathological markers of the disease.Brain tissue from individuals with sporadic Creutzfeldt-Jakob disease and age-matched controls were obtained from the brain collection of the Austrian Creutzfeldt-Jakob Surveillance. The mitochondrial respiratory chain was studied through a dichotomous approach of immunoreactivities in the temporal cortex and the hippocampal subregions of CA4 and CA3.We show that profound deficiency of all mitochondrial respiratory complexes (I-V) occurs in neurons of the severely affected temporal cortex of patients with Creutzfeldt-Jakob disease. This deficiency correlates strongly with the severity of neuropathological changes, including vacuolation of the neuropil, gliosis and disease associated prion protein load. Respiratory chain deficiency is less pronounced in hippocampal CA4 and CA3 regions compared to the temporal cortex. In both areas respiratory chain deficiency shows a predilection for the MM1 molecular subtype of Creutzfeldt-Jakob disease.Our findings indicate that aberrant mitochondrial respiration could be involved early in the pathogenesis of sporadic Creutzfeldt-Jakob disease and contributes to neuronal death, most likely via ATP depletion. Based on these results, we propose that the restricted MRI diffusion profile seen in the brain of patients with sporadic Creutzfeldt-Jakob disease might reflect cytotoxic changes due to neuronal respiratory chain failure and ATP loss.

Quantitative Measurement of the Improvement Derived From a 10-Mo Progressive Exercise Program to Improve Balance and Function in Women at Increased Risk for Fragility Fractures.

INTRODUCTION/BACKGROUND: Osteoporosis is a common disorder and is associated with an increased risk of bone fracture. Falls are a proximate cause of a high proportion of medical costs and mortality. Improving balance can reduce the risk of falls and improve health outcomes, especially for the at-risk population of people with osteoporosis and osteopenia. The FrameWorksTM exercise program is a formal, standardized, informational and interventional 10-month exercise program. The purpose of this study was to quantitatively assess the improvement in standing balance, functional reach, and overall confidence in balance after participating in the 10-month program. METHODOLOGY: This study is a prospectively designed study with a pre and post study measurement of balance metrics. Sixty-two female participants, 45 years of age or older and at increased risk for fragility fractures, completed the 10-month program as well the pre and post program testing. Confidence was measured with the Activities-specific Balance Confidence Scale, a self-reported survey. Balance was measured digitally by means of testing with a NeuroCom® Basic Balance Master® system. Measurements were made of the Limits of Stability (LOS) Test and Modified Clinical Test of Sensory Interaction on Balance (mCTSIB). Balance was clinically assessed with the Functional Reach Test (FRT). RESULTS: Participation in the 10 months FrameWorksTM program resulted in improvement in quantitative measures of balance (Composite Sway Velocity, -12%, p < 0.001; End point excursion, 17.1%, p < 0.000001). A clinical measure of balance, the Functional Reach Test, improved, (2.9 cm, p < 0.0001). Participation also resulted in improvement in balance confidence (9.4 %, p < 0.00001). A height increase was observed (0.6 cm, p < 0.000001). CONCLUSIONS: The 10-month FrameWorksTM program improves balance and confidence in women at risk for fragility fractures. By improving balance and confidence, people are less likely to fall and therefore sustain fewer fractures and associated injuries.

Circulating Tumor Biomarkers in Meningiomas Reveal a Signature of Equilibrium Between Tumor Growth and Immune Modulation.

Meningiomas are primary central nervous system (CNS) tumors that originate from the arachnoid cells of the meninges. Recurrence occurs in higher grade meningiomas and a small subset of Grade I meningiomas with benign histology. Currently, there are no established circulating tumor markers which can be used for diagnostic and prognostic purposes in a non-invasive way for meningiomas. Here, we aimed to identify potential biomarkers of meningioma in patient sera. For this purpose, we collected preoperative (n = 30) serum samples from the meningioma patients classified as Grade I (n = 23), Grade II (n = 4), or Grade III (n = 3). We used a high-throughput, multiplex immunoassay cancer panel comprising of 92 cancer-related protein biomarkers to explore the serum protein profiles of meningioma patients. We detected 14 differentially expressed proteins in the sera of the Grade I meningioma patients in comparison to the age- and gender-matched control subjects (n = 12). Compared to the control group, Grade I meningioma patients showed increased serum levels of amphiregulin (AREG), CCL24, CD69, prolactin, EGF, HB-EGF, caspase-3, and decreased levels of VEGFD, TGF-α, E-Selectin, BAFF, IL-12, CCL9, and GH. For validation studies, we utilized an independent set of meningioma tumor tissue samples (Grade I, n = 20; Grade II, n = 10; Grade III, n = 6), and found that the expressions of amphiregulin and Caspase3 are significantly increased in all grades of meningiomas either at the transcriptional or protein level, respectively. In contrast, the gene expression of VEGF-D was significantly lower in Grade I meningioma tissue samples. Taken together, our study identifies a meningioma-specific protein signature in blood circulation of meningioma patients and highlights the importance of equilibrium between tumor-promoting factors and anti-tumor immunity.

Neuropathology-driven Whole-genome Sequencing Study Points to Novel Candidate Genes for Healthy Brain Aging.

PURPOSE: Understanding the healthy brain aging process is key to uncover the mechanisms that lead to pathologic age-related neurodegeneration, including progression to Alzheimer disease (AD). We aimed to address the issue of pathologic heterogeneity that often underlies a clinical AD diagnosis. METHODS: We performed a deep whole-genome sequencing study aiming to identify variants that are associated specifically with healthy brain aging. PATIENTS: We examined samples from the community-based longitudinal Vienna Transdanubian Aging study comparing neuropathologically "healthy" aging in individuals above 80 years of age with pure AD patients of the same age. RESULTS: Focusing on potentially functional variants, we discovered a single variant (rs10149146) that lies on the autophagy-associated TECPR2 gene and was carried by 53.6% of the "healthy" brain elderly individuals (15/28). An additional nonsynonymous variant on the CINP gene (encoding a cell cycle checkpoint protein) was also found in 46% of healthy controls. Both variants are absent from all AD cases. TECPR2 and CINP appear to be "partner" genes in terms of regulation and their associated transcription factors have been previously implicated in AD and neurodegeneration. CONCLUSIONS: Our study underlines the strength of neuropathology-driven definitions in genetic association studies and points to a potentially neuroprotective effect of key molecules of autophagy and cell cycle control.

The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space.

Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.

Molecular diagnostic testing of diffuse gliomas in the real-life setting: A practical approach.

Typing of diffuse gliomas according to the WHO 2016 Classification of Tumors of the Central Nervous System is based on the integration of histology with molecular biomarkers. However, the choice of appropriate methods for molecular analysis and criteria for interpretation of test results is left to each diagnostic laboratory. In the present study, we tested the applicability of combined immunohistochemistry, direct sequencing, and multiplex ligation-dependent probe amplification (MLPA) for diagnostic assessment of IDH1/2 mutation status, chromosome 1p/19q status, and TERT promoter mutations. To this end, we analyzed a consecutive series of 165 patients with diffuse low- and high-grade gliomas (WHO grade II and III) from three Austrian centers in which tissue specimens were routinely processed. We could reliably detect IDH1/2 mutations by combining immunohistochemistry, direct sequencing, and MLPA analysis. MLPA analysis also allowed reliable detection of combined whole chromosomal arm 1p/19q codeletion when using carefully selected criteria providing an optimal balance between sensitivity and specificity. Direct sequencing proved to be suitable for identification of TERT promoter mutations, although its analytical performance remains to be assessed. To conclude, we propose a practicable combination of methods and criteria which allow reliable molecular diagnostic testing of diffuse gliomas in the real-life setting.
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Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma.

Ape1 is the major apurinic/apyrimidinic (AP) endonuclease activity in mammalian cells, and a key factor in base-excision repair of DNA. High expression or aberrant subcellular distribution of Ape1 has been detected in many cancer types, correlated with drug response, tumor prognosis, or patient survival. Here we present evidence that Ape1 facilitates BRCA1-mediated homologous recombination repair (HR), while counteracting error-prone non-homologous end joining of DNA double-strand breaks. Furthermore, Ape1, coordinated with checkpoint kinase Chk2, regulates drug response of glioblastoma cells. Suppression of Ape1/Chk2 signaling in glioblastoma cells facilitates alternative means of damage site recruitment of HR proteins as part of a genomic defense system. Through targeting "HR-addicted" temozolomide-resistant glioblastoma cells via a chemical inhibitor of Rad51, we demonstrated that targeting HR is a promising strategy for glioblastoma therapy. Our study uncovers a critical role for Ape1 in DNA repair pathway choice, and provides a mechanistic understanding of DNA repair-supported chemoresistance in glioblastoma cells.

Overexpression of minichromosome maintenance protein 10 in medulloblastoma and its clinical implications.

BACKGROUND: Overexpression of minichromosome maintenance (MCM) proteins 2, 3, and 7 is associated with migration and invasion in medulloblastoma (MB). However, expression profiling of all prereplication complex (pre-RC) has not been addressed in MBs. PROCEDURE: We performed mRNA expression profiling of a large set of pre-RC elements in cell lines and tumor tissues of MB. RNAi technology was employed for functional studies in MB cell lines. RESULTS: Our data showed that most of the pre-RC components are significantly overexpressed in MB. Among all pre-RC mRNAs, MCM10 showed the highest level of expression (∼500- to 1,000-fold) in MB cell lines and tissues compared to the levels detected in cerebellum. In addition, RNAi silencing of MCM10 caused reduced cell proliferation and cell viability in MB cells. CONCLUSIONS: Taken together, our study reveals that the pre-RC is dysregulated in MB. In addition, MCM10, a member of this complex, is significantly overexpressed in MB and is required for tumor cell proliferation.

Tau pathology in Creutzfeldt-Jakob disease revisited.

Creutzfeldt-Jakob disease (CJD) is a human prion disease with different etiologies. To determine the spectrum of tau pathologies in CJD, we assessed phospho-Tau (pTau) immunoreactivities in 75 sporadic CJD cases including an evaluation of the entorhinal cortex and six hippocampal subregions. Twelve cases (16%) showed only small tau-immunoreactive neuritic profiles. Fifty-two (69.3%) showed additional tau pathology in the medial temporal lobe compatible with primary age related tauopathy (PART). In 22/52 cases the lower pTau immunoreactivity load in the entorhinal cortex as compared to subiculum, dentate gyrus or CA4 region of the hippocampus was significantly different from the typical distribution of the Braak staging. A further 11 cases (14.7%) showed widespread tau pathologies compatible with features of primary tauopathies or the gray matter type of ageing-related tau astrogliopathy (ARTAG). Prominent gray matter ARTAG was also observed in two out of three additionally examined V203I genetic CJD cases. Analysis of cerebrospinal fluid revealed prominent increase of total tau protein in cases with widespread tau pathology, while pTau (T181) level was increased only in four. This correlated with immunohistochemical observations showing less pathology with anti-pTau T181 antibody when compared to anti-pTau S202/T205, T212/S214 and T231. The frequency of tau pathologies is not unusually high in sporadic CJD and does not precisely relate to PrP deposition. However, the pattern of hippocampal tau pathology often deviates from the stages of Braak. Currently applied examination of cerebrospinal fluid pTau (T181) level does not reliably reflect primary tauopathies, PART and ARTAG seen in CJD brains.

Familial early-onset dementia with complex neuropathologic phenotype and genomic background.

Despite significant progress in our understanding of hereditary neurodegenerative diseases, the list of genes associated with early-onset dementia is not yet complete. In the present study, we describe a familial neurodegenerative disorder characterized clinically as the behavioral and/or dysexecutive variant of Alzheimer's disease with neuroradiologic features of Alzheimer's disease, however, lacking amyloid-ß deposits in the brain. Instead, we observed a complex, 4 repeat predominant, tauopathy, together with a TAR DNA-binding protein of 43 kDa proteinopathy. Whole-exome sequencing on 2 affected siblings and 1 unaffected aunt uncovered a large number of candidate genes, including LRRK2 and SYNE2. In addition, DDI1, KRBA1, and TOR1A genes possessed novel stop-gain mutations only in the patients. Pathway, gene ontology, and network interaction analysis indicated the involvement of pathways related to neurodegeneration but revealed novel aspects also. This condition does not fit into any well-characterized category of neurodegenerative disorders. Exome sequencing did not disclose a single disease-specific gene mutation suggesting that a set of genes working together in different pathways may contribute to the etiology of the complex phenotype.

Dura mater is a potential source of Aß seeds.

Deposition of amyloid-ß (Aß) in the brain parenchyma and vessels is one of the hallmarks of Alzheimer disease (AD). Recent observations of Aß deposition in iatrogenic Creutzfeldt-Jakob disease (iCJD) after dural grafting or treatment with pituitary extracts raised concerns whether Aß is capable of transmitting disease as seen in prion diseases by the disease-associated prion protein. To address this issue, we re-sampled and re-evaluated archival material, including the grafted dura mater of two cases with iCJD (28 and 33-years-old) without mutations in the AßPP, PSEN1 and PSEN2 genes, and carrying ε3/ε3 alleles of the APOE gene. In addition, we evaluated 84 dura mater samples obtained at autopsy (mean age 84.9 ± 0.3) in the community-based VITA study for the presence of Aß deposition. We show that the dura mater may harbor Aß deposits (13 %) in the form of cerebral amyloid angiopathy or amorphous aggregates. In both iCJD cases, the grafted dura mater had accumulated Aß. The morphology and distribution pattern of cerebral Aß deposition together with the lack of tau pathology distinguishes the Aß proteinopathy in iCJD from AD, from that seen in young individuals without cognitive decline carrying one or two APOE4 alleles, and from that related to traumatic brain injury. Our novel findings of Aß deposits in the dura mater, including the grafted dura, and the distinct cerebral Aß distribution in iCJD support the seeding properties of Aß. However, in contrast to prion diseases, our study suggests that such Aß seeding is unable to reproduce the full clinicopathological phenotype of AD.