Trigger point injections followed by immediate myofascial release in the treatment of pelvic floor tension myalgia.

PURPOSE: Pelvic floor physical therapy (PFPT) is first-line therapy for treatment of pelvic floor tension myalgia (PFTM). Pelvic floor trigger point injections (PFTPI) are added if symptoms are refractive to conservative therapy or if patients experience a flare. The primary objective was to determine if a session of physical therapy with myofascial release immediately following PFTPI provides improved pain relief compared to trigger point injection alone. METHODS: This was a retrospective cohort analysis of 87 female patients with PFTM who underwent PFTPI alone or PFTPI immediately followed by PFPT. Visual analog scale (VAS) pain scores were recorded pre-treatment and 2 weeks post-treatment. The primary outcome was the change in VAS between patients who received PFTPI alone and those who received PFTPI followed by myofascial release. RESULTS: Of the 87 patients in this study, 22 received PFTPI alone and 65 patients received PFTPI followed by PFPT. The median pre-treatment VAS score was 8 for both groups. The median post-treatment score was 6 for the PFTPI only group and 4 for the PFTPI followed by PFPT group, showing a median change in VAS score of 2 and 4, respectively (p = 0.042). Seventy-seven percent of patients in the PFTPI followed by PFPT group had a VAS score improvement of 3 or more, while 45% of patients in the PFTPI only group had a VAS score improvement greater than 3 (p = 0.008). CONCLUSION: PFTPI immediately followed by PFPT offered more improvement in pain for patients with PFTM. This may be due to greater tolerance of myofascial release immediately following injections.

Phosphorylated tau sites that are elevated in Alzheimer's disease fluid biomarkers are visualized in early neurofibrillary tangle maturity levels in the post mortem brain.

INTRODUCTION: Alzheimer's disease (AD) biomarkers are increasingly more reliable in predicting neuropathology. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, we sought to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) are recognized. METHODS: We queried the Florida Autopsied Multi-Ethnic (FLAME) cohort for cases ranging from Braak stages I through VI, excluding non-AD neuropathologies and tauopathies. Thioflavin-S staining was compared to immunohistochemical measures of phosphorylated threonine (pT) 181, pT205, pT217, and pT231 in two hippocampal subsectors across n = 24 cases. RESULTS: Each phosphorylated tau site immunohistochemically labeled early neurofibrillary tangle maturity levels compared to advanced levels recognized by thioflavin-S. Hippocampal burden generally increased with each Braak stage. DISCUSSION: These results provide neurobiologic evidence that these phosphorylated tau fluid biomarker sites are present during early neurofibrillary tangle maturity levels and may explain why these fluid biomarker measures are observed before symptom onset. HIGHLIGHTS: Immunohistochemical evaluation of four phosphorylated tau fluid biomarker sites. Earlier neurofibrillary tangle maturity levels recognized by phosphorylated tau in proline-rich region. Advanced tangle pathology is elevated in the subiculum compared to the cornu ammonis 1 of the hippocampus. Novel semi-quantitative frequency to calculate tangle maturity frequency.

Latent trait modeling of tau neuropathology in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson's disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10-5) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.

Comparison of endoscopic ultrasound-guided fine-needle biopsy versus fine-needle aspiration for genomic profiling and DNA yield in pancreatic cancer: a randomized crossover trial.

BACKGROUND: National guidelines recommend genomic profiling of tumor tissue to guide precision therapy. We compared the specimen adequacy for genomic profiling and yield of DNA between endoscopic ultrasound (EUS)-guided fine-needle biopsy (FNB) and EUS-guided fine-needle aspiration (FNA). METHODS: In our tandem, randomized controlled trial, consecutive patients undergoing EUS for evaluation of pancreatic masses underwent both conventional EUS-FNA with a 25-gauge needle and paired EUS-FNB (19 or 22-gauge needle), with the order randomized (EUS-FNA first followed by EUS-FNB, or vice versa). A minimum of one pass with each needle was obtained for histology. Second and third passes were performed to collect DNA. Specimens were evaluated by a cytopathologist blinded to the needle type. Specimen adequacy for genomic profiling was calculated based on FoundationOne clinical diagnostic (CDx) adequacy requirements. We compared the adequacy for genomic profiling DNA (quantity) and histology yields with both needles. RESULTS: Analysis included 50 patients (25 men; mean age 68 [standard deviation (SD) 13] years), with a mean lesion size of 38 (SD 17) mm; 37 lesions (74 %) were pancreatic ductal adenocarcinoma (PDAC). The mean DNA concentrations in PDAC by FNB and FNA needles were 5.930 (SD 0.881) µg/mL vs. 3.365 (SD 0.788) µg/mL, respectively (P = 0.01). The median standardized histology score per pass with EUS-FNB was 5 (sufficient for histology) and for EUS-FNA was 2 (enough for cytology). Specimen adequacy for genomic profiling and yield of DNA was significantly higher with FNB than with FNA needles. CONCLUSIONS: In this study, adequacy for genomic profiling, DNA, and histology yield were considerably superior using an EUS-FNB needle compared with an EUS-FNA needle.

Mental Health and Chemical Dependency Services at US Cancer Centers.

BACKGROUND: It is standard of care and an accreditation requirement to screen for and address distress and psychosocial needs in patients with cancer. This study assessed the availability of mental health (MH) and chemical dependency (CD) services at US cancer centers. METHODS: The 2017-2018 American Hospital Association (AHA) survey, Area Health Resource File, and Centers for Medicare & Medicaid Services Hospital Compare databases were used to assess availability of services and associations with hospital-level and health services area (HSA)-level characteristics. RESULTS: Of 1,144 cancer centers surveyed, 85.4% offered MH services and 45.5% offered CD services; only 44.1% provided both. Factors associated with increased adjusted odds of offering MH services were teaching status (odds ratio [OR], 1.76; 95% CI, 1.18-2.62), being a member of a hospital system (OR, 2.00; 95% CI, 1.31-3.07), and having more beds (OR, 1.04 per 10-bed increase; 95% CI, 1.02-1.05). Higher population estimate (OR, 0.98; 95% CI, 0.97-0.99), higher percentage uninsured (OR, 0.90; 95% CI, 0.86-0.95), and higher Mental Health Professional Shortage Area level in the HSA (OR, 0.99; 95% CI, 0.98-1.00) were associated with decreased odds of offering MH services. Government-run (OR, 2.85; 95% CI, 1.30-6.22) and nonprofit centers (OR, 3.48; 95% CI, 1.78-6.79) showed increased odds of offering CD services compared with for-profit centers. Those that were members of hospital systems (OR, 1.61; 95% CI, 1.14-2.29) and had more beds (OR, 1.02; 95% CI, 1.01-1.03) also showed increased odds of offering these services. A higher percentage of uninsured patients in the HSA (OR, 0.92; 95% CI, 0.88-0.97) was associated with decreased odds of offering CD services. CONCLUSIONS: Patients' ability to pay, membership in a hospital system, and organization size may be drivers of decisions to co-locate services within cancer centers. Larger organizations may be better able to financially support offering these services despite poor reimbursement rates. Innovations in specialty payment models highlight opportunities to drive transformation in delivering MH and CD services for high-need patients with cancer.

Comparative Effects of Physical Exercise and Other Behavioral Interventions on Functional Status Outcomes in Mild Cognitive Impairment.

OBJECTIVES: Lifestyle modifications for those with mild cognitive impairment (MCI) may promote functional stability, lesson disease severity, and improve well-being outcomes such as quality of life. The current analysis of our larger comparative effectiveness study evaluated which specific combinations of lifestyle modifications offered as part of the Mayo Clinic Healthy Action to Benefit Independence in Thinking (HABIT) program contributed to the least functional decline in people with MCI (pwMCI) over 18 months. METHODS: We undertook to compare evidence-based interventions with one another rather than to a no-treatment control group. The interventions were five behavioral treatments: computerized cognitive training (CCT), yoga, Memory Support System (MSS) training, peer support group (SG), and wellness education (WE), each delivered to both pwMCI and care partners, in a group-based program. To compare interventions, we randomly withheld one of the five HABIT® interventions in each of the group sessions. We conducted 24 group sessions with between 8 and 20 pwMCI-partner dyads in a session. RESULTS: Withholding yoga led to the greatest declines in functional ability as measured by the Functional Activities Questionnaire and Clinical Dementia Rating. In addition, memory compensation (calendar) training and cognitive exercise appeared to have associations (moderate effect sizes) with better functional outcomes. Withholding SG or WE appeared to have little effect on functioning at 18 months. CONCLUSIONS: Overall, these results add to the growing literature that physical exercise can play a significant and lasting role in modifying outcomes in a host of medical conditions, including neurodegenerative diseases.

Timeline and location of recurrence following successful ablation in Barrett's oesophagus: an international multicentre study.

OBJECTIVE: Surveillance interval protocols after complete remission of intestinal metaplasia (CRIM) post radiofrequency ablation (RFA) in Barrett's oesophagus (BE) are currently empiric and not based on substantial evidence. We aimed to assess the timeline, location and patterns of recurrence following CRIM to inform these guidelines. DESIGN: Data on patients undergoing RFA for BE were obtained from prospectively maintained databases of five (three USA and two UK) tertiary referral centres. RFA was performed until CRIM was confirmed on two consecutive endoscopies. RESULTS: 594 patients achieved CRIM as of 1 May 2017. 151 subjects developed recurrent BE over a median (IQR) follow-up of 2.8 (1.4-4.4) years. There was 19% cumulative recurrence risk of any BE within 2 years and an additional 49% risk over the next 8.6 years. There was no evidence of a clinically meaningful change in the recurrence hazard rate of any BE, dysplastic BE or high-grade dysplasia/cancer over the duration of follow-up, with an estimated 2% (95% CI -7% to 12%) change in recurrence rate of any BE in a doubling of follow-up time. 74% of BE recurrences developed at the gastro-oesophageal junction (GOJ) (24.1% were dysplastic) and 26% in the tubular oesophagus. The yield of random biopsies from the tubular oesophagus, in the absence of visible lesions, was 1% (BE) and 0.2% (dysplasia). CONCLUSIONS: BE recurrence risk following CRIM remained constant over time, suggesting that lengthening of follow-up intervals, at least in the first 5 years after CRIM, may not be advisable. Sampling the GOJ is critical to detecting recurrence. The requirement for random biopsies of the neosquamous epithelium in the absence of visible lesions may need to be re-evaluated.

Ethnoracial differences in Alzheimer's disease from the FLorida Autopsied Multi-Ethnic (FLAME) cohort.

INTRODUCTION: Our primary goal was to examine demographic and clinicopathologic differences across an ethnoracially diverse autopsy-confirmed cohort of Alzheimer's disease cases. METHODS: A retrospective study was conducted in the Florida Autopsied Multi-Ethnic cohort on 1625 Alzheimer's disease cases, including decedents who self-reported as Hispanic/Latino (n = 67), black/African American (n = 19), and white/European American (n = 1539). RESULTS: Hispanic decedents had a higher frequency of family history of cognitive impairment (58%), an earlier age at onset (median age of 70 years), longer disease duration (median of 12 years), and lower MMSE proximal to death (median of 4 points) compared with the other ethnoracial groups. Black decedents had a lower Braak tangle stage (stage V) and higher frequency of coexisting hippocampal sclerosis (21%); however, only hippocampal sclerosis differences survived adjustment for sex, age at onset, and disease duration. Neither Thal amyloid phase nor coexisting Lewy body disease differed across ethnoracial groups. DISCUSSION: Despite a smaller sample size, Hispanics demonstrated longer disease duration with Alzheimer's disease, but not greater lifespan. Neuropathologic differences across ethnoracial groups supported differences in tau pathology distribution and coexisting hippocampal sclerosis, which may impact biomarker studies.

Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by tau pathology in neurons and glial cells. Transcriptional regulation has been implicated as a potential mechanism in conferring disease risk and neuropathology for some PSP genetic risk variants. However, the role of transcriptional changes as potential drivers of distinct cell-specific tau lesions has not been explored. In this study, we integrated brain gene expression measurements, quantitative neuropathology traits and genome-wide genotypes from 268 autopsy-confirmed PSP patients to identify transcriptional associations with unique cell-specific tau pathologies. We provide individual transcript and transcriptional network associations for quantitative oligodendroglial (coiled bodies = CB), neuronal (neurofibrillary tangles = NFT), astrocytic (tufted astrocytes = TA) tau pathology, and tau threads and genomic annotations of these findings. We identified divergent patterns of transcriptional associations for the distinct tau lesions, with the neuronal and astrocytic neuropathologies being the most different. We determined that NFT are positively associated with a brain co-expression network enriched for synaptic and PSP candidate risk genes, whereas TA are positively associated with a microglial gene-enriched immune network. In contrast, TA is negatively associated with synaptic and NFT with immune system transcripts. Our findings have implications for the diverse molecular mechanisms that underlie cell-specific vulnerability and disease risk in PSP.

ERAS protocol validation in a propensity-matched cohort of patients undergoing colorectal surgery.

PURPOSE: Enhanced recovery after surgery (ERAS) provides many benefits. However, important knowledge gaps with respect to specific components of enhanced recovery after surgery remain because of limited validation data. The aim of the study was to validate a mature ERAS protocol at a different hospital and in a similar population of patients. METHODS: This is a retrospective analysis of patients undergoing elective colorectal surgery from 2009 through 2016. Patients enrolled in ERAS are compared with those undergoing the standard of care. Patient demographic characteristics, length of stay, pain scores, and perioperative morbidity are described. RESULTS: Patients (1396) were propensity matched into two equal groups (ERAS vs non-ERAS). No significant difference was observed for age, Charlson Comorbidity Index, American Society of Anesthesiologists score, body mass index, sex, operative approach, and surgery duration. Median length of stay in ERAS and non-ERAS groups was 3 and 5 days (P < .001). Mean pain scores were lower in the ERAS group, measured at discharge from the postanesthesia unit (P < .001), on postoperative day 1 (P = .002) and postoperative day 2 (P = .02) but were identical on discharge. CONCLUSIONS: This ERAS protocol was validated in a similar patient population but at a different hospital. ERAS implementation was associated with an improved length of stay and pain scores similar to the original study. Different than most retrospective studies, propensity score matching ensured that groups were evenly matched. To our knowledge, this study is the only ERAS validation study in a propensity-matched cohort of patients undergoing elective colorectal surgery.

The limbic and neocortical contribution of α-synuclein, tau, and amyloid ß to disease duration in dementia with Lewy bodies.

INTRODUCTION: We sought to assess the individual and combined contribution of limbic and neocortical α-synuclein, tau, and amyloid ß (Aß) to duration of illness in dementia with Lewy bodies (DLB). METHODS: Quantitative digital pathology of limbic and neocortical α-synuclein, tau, and Aß was assessed in 49 patients with clinically probable DLB. Regression modeling examined the unique and shared contribution of each pathology to the variance of illness duration. RESULTS: Patients with diffuse Lewy body disease had more severe pathology of each type and a shorter duration of illness than individuals with transitional Lewy body disease. The three pathologies accounted for 25% of the total variance of duration of illness, with 19% accounted for by α-synuclein alone or in combination with tau and Aß. When the diffuse Lewy body disease group was examined separately, α-synuclein deposition significantly exceeded that of tau and Aß. In this model, 20% of 24% total variance in the model for duration of illness was accounted for independently by α-synuclein. DISCUSSION: In DLB, α-synuclein is an important predictor of disease duration, both independently and synergistically with tau and Aß.

Genome-wide association study of cardiotoxicity in the NCCTG N9831 (Alliance) adjuvant trastuzumab trial.

OBJECTIVES: The major clinical side effect of the ERBB2-targeted breast cancer therapy, trastuzumab, is a decline in the left ventricular ejection fraction (LVEF). Improved markers are needed to better identify patients susceptible to cardiotoxicity. METHODS: The NCCTG N9831 trial compared adjuvant doxorubicin and cyclophosphamide followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or concurrent paclitaxel and trastuzumab (arm C) in patients with HER2-positive breast cancer. A genome-wide association study was performed on all patients with available DNA (N=1446). We used linear regression to identify single nucleotide polymorphisms (SNPs) associated with decline in LVEF, adjusting for age, baseline LVEF, antihypertensive medications, and the first two principle components. RESULTS: In total, 618 863 SNPs passed quality control and DNA from 1191 patients passed genotyping quality control and were identified as Whites of non-Hispanic origin. SNPs at six loci were associated with a decline in LVEF (P=7.73×10 to 8.93×10), LDB2, BRINP1, chr6 intergenic, RAB22A, TRPC6, and LINC01060, in patients who received chemotherapy plus trastuzumab (arms BC, N=800). None of these loci were significant in patients who received chemotherapy only (arm A, N=391) and did not increase in significance in the combined analysis of all patients. We did not observe association, P<0.05, with SNPs previously associated with trastuzumab-induced cardiotoxicity at ERBB2, I655V, and P1170A. We replicated association, P<0.05, with SNPs previously associated with anthracycline-induced cardiotoxicity at CBR3 and ABCB1. CONCLUSION: Our study identified six putative novel cardiotoxicity loci in patients treated with combination chemotherapy and trastuzumab that require further investigation and confirmed known associations of anthracycline-induced cardiotoxicity.

Effect of an endoscopic quality improvement program on adenoma detection rates: a multicenter cluster-randomized controlled trial in a clinical practice setting (EQUIP-3).

BACKGROUND: Colonoscopy is protective against colorectal cancer, but its quality and protective benefits can vary. Adenoma detection rate (ADR) is associated with quality and the degree of protection against colorectal cancer and death. In a previous, single academic center, randomized, controlled trial, we demonstrated that an endoscopic quality improvement program increased ADR (EQUIP-1) and that those increases were durable (EQUIP-2). We hypothesized that EQUIP training would increase ADR in a multicenter clinical practice setting. METHODS: Nine large clinical practice sites were recruited. After a baseline period (phase I), 5 sites were randomized to receive supplemental in-person EQUIP training with active feedback. After follow-up (phase II), the changes in ADRs at these sites were compared with the changes at 4 control sites that did not receive training or feedback until after study completion. RESULTS: Twenty-two thousand three hundred sixteen colonoscopies were included. There was a statistically significant increase in ADR at the training sites (odds ratio [OR], 1.28; P = .004) with a raw ADR of 31% in phase I and 42% in phase II after the intervention. However, raw ADRs also increased at the control sites (from 36% to 39%). As a result, there was limited evidence of a training effect (OR, 1.03; 95% confidence interval [CI], 0.84-1.25; P = .78). CONCLUSIONS: ADRs increased at the sites participating in the endoscopic quality improvement program. However it is not clear to what extent the training program is responsible for the changes, because raw ADRs also increased at the control sites but to a lesser extent. (Clinical Trials Registration number: NCT02325635.).

Impact of an Endoscopic Quality Improvement Program Focused on Adenoma Detection on Sessile Serrated Adenoma/Polyp Detection.

BACKGROUND: Sessile serrated adenomas/polyps (SSA/P) are an under-recognized disease with a unique malignant pathway. Improved endoscopic recognition and pathological interpretation is needed. AIMS: To determine whether an educational intervention that improved adenoma detection rate (ADR) could improve SSA/P detection rate after reclassification of previously termed "hyperplastic" polyps. METHODS: We reanalyzed data from a prospective randomized trial of an educational intervention aimed at increasing ADR. All hyperplastic polyps ≥6 mm reported in a previously published study were rereviewed and reclassified using standardized criteria for serrated lesions. Detection rates of sessile serrated adenomas/polyps and other clinically relevant serrated polyps were calculated in the baseline and post-training phases of the original study. RESULTS: Of 263 available for rereview, 33 (12.5%) were reclassified as SSA/P (N = 32) or traditional serrated adenoma (TSA) (N = 1). Reclassification was more common in the right colon (18 vs. 8%, p = 0.02). Baseline SSA/P detection rate was 0.7% in the untrained group and 1.3% in the trained group. Post-training, the SSA/P detection rate increased to 2.1 and 1.5%, respectively. The clinically relevant serrated polyp detection rate at baseline was 14.2% in the untrained group and 11.3% in the trained group. After the educational intervention, the clinically relevant serrated polyp detection rates increased to 16.5 and 14.8% in the untrained and trained groups, respectively. The estimated odds of an endoscopist detecting either a SSA/P or other clinically relevant serrated polyp during colonoscopy increased by only 3% with the educational intervention (OR 1.03, 95% CI 0.61-1.74, p = 0.91). CONCLUSIONS: Pathological re-interpretation of larger serrated polyps resulted in the reclassification of 12.5% of lesions. Quality improvement methods focused on adenoma detection did not impact SSA/P detection, and thus specific methods for serrated polyp detection are needed.

Timing interval from peri-prostatic block to biopsy impacts procedural pain.

INTRODUCTION: To compare visual analog scale (VAS) pain scores between patients with a 2-minute versus 10-minute delay of peri-prostatic lidocaine injection prior to transrectal ultrasound-guided prostate biopsies (TRUS-bx). MATERIALS AND METHODS: Eighty patients who underwent standard 12-core TRUS-bx by a single surgeon were prospectively randomized into four different treatment arms: bibasilar injection with a 2-minute delay, bibasilar injection plus a single apical injection with a 2-minute delay, bibasilar injection with a 10-minute delay, and bibasilar injection plus a single apical injection with a 10-minute delay. Patients were asked to report their level of pain on the VAS (0-10, with 10 indicating unbearable pain) at the following intervals: probe insertion (baseline), after each core, and post-procedure. The primary outcome measure was mean VAS score across all 12 cores minus baseline VAS score, which we refer to baseline-adjusted mean VAS score. RESULTS: Baseline-adjusted mean VAS score was significantly higher for the 2-minute delay group compared to the 10-minute delay group (mean: -0.7 versus -1.6, p = 0.025). Subset analysis of biopsies 1-3, 4-6, 7-9 and 10-12 also demonstrated higher baseline-adjusted mean VAS scores in the 2-minute delay group (all p ≤ 0.043). CONCLUSIONS: Lower TRUS-bx VAS scores can be achieved by extending the time from lidocaine injection to onset of prostate biopsy from 2 to 10 minutes.

A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression.

INTRODUCTION: We hypothesized that common Alzheimer's disease (AD)-associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression. METHODS: Expression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis. RESULTS: A variant within a DNase hypersensitive site 5' of TREM2, rs9357347-C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10-3 and 4.6 × 10-2, respectively). Meta-analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 × 10-2 and 3.5 × 10-3, Bonferroni-corrected P = 6.7 × 10-2 and 7.1 × 10-3, respectively). DISCUSSION: Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome-wide association study meta-analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD.

Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease (AD). APOE4 is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, we examined the effects of APOE4, sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (n = 60) or without CAA (n = 39) were subjected to biochemical analysis of amyloid-ß (Aß) and apolipoprotein E (apoE) by ELISA in the temporal cortex. After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, we found that overall CAA scores were higher in males than females. Furthermore, carrying one or more APOE4 alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent-soluble and detergent-insoluble Aß40, and insoluble apoE were significantly elevated in individuals with severe CAA or APOE4. The ratio of Aß40/Aß42 in insoluble fractions was also increased in the presence of CAA or APOE4, although it was negatively associated with male sex. Levels of insoluble Aß40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble Aß42, the levels of apoE correlated regardless of CAA status. Our results indicate that sex and APOE genotypes differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of Aß40 and apoE.

Neuropathologic differences by race from the National Alzheimer's Coordinating Center.

INTRODUCTION: Compared to Caucasians, African Americans (AAs) have higher dementia prevalence, different genetic markers, and higher vascular risk factors. However, pathologic underpinnings are unknown. METHODS: We used neuropathologic and clinical data on 110 AA and 2500 Caucasians who were demented before death. The groups were compared regarding demographics, cognition, apolipoprotein E (APOE) genotype, comorbidities, and clinical and neuropathologic characteristics. RESULTS: AA and Caucasians differed in their demographics, cognition at the last visit before death, APOE genotype, presence of hypertension, primary clinical diagnoses, and AD, cerebrovascular disease (CVD), and other neuropathologies such as Lewy body disease (LBD). DISCUSSION: AD, LBD, and CVD pathology were more common and TDP and frontotemporal lobar degeneration-tau less common in AA than in Caucasians. APOE accounted for most of the AD neuropathologic differences. If replicated, the observed differences in underlying neuropathology by race will be important for public health policy and recruitment for and interpreting of clinical trials.

Stability of increased adenoma detection at colonoscopy. Follow-up of an endoscopic quality improvement program-EQUIP-II.

OBJECTIVES: We recently completed a randomized controlled trial of an endoscopic quality improvement program (EQUIP) that demonstrated an improved adenoma detection rate (ADR) through simple educational interventions. The aim of this study (phase III) is to examine whether the improvement in ADR in the trained endoscopists remained stable with further follow-up. METHODS: We prospectively followed up 15 staff endoscopists who had previously been randomized to a quality improvement intervention. In the current study, we examined an additional 1,200 colonoscopy procedures conducted over a 5-month time period following the original study, referred to as phase III. During this time, all physicians received quarterly ADR and other quality metric feedback, and the previous control group was offered the educational intervention voluntarily. ADRs and adenoma per patient (APP) rates were estimated in the endoscopists who were and were not randomized to EQUIP training and compared with those obtained in phases I and II of the original study. The study was conducted in a tertiary care Academic Medical Center. The study sample comprised 1200 patients undergoing routine colonoscopy. The main outcome measurement was adenoma detection rate. RESULTS: The previously observed increase in ADR in the trained group from 36% in phase I to 47% in phase II was maintained into phase III (46%). The ADR of the untrained group remained unchanged from phase I (36%) to phase II (35%); it was increased only marginally in phase III to 39%, which was still lower than the 46% ADR in the trained group. The trained group had an increase in APP, from 0.72 in Phase I to 0.87 in Phase II and 0.98 in Phase III. For the previously untrained group, there was no change in APP from phase I (0.68) to phase II (0.68), but there was possibly a small increase (to 0.74) in Phase III. CONCLUSIONS: This study provides evidence that improvements in ADR obtained through the endoscopic quality-training program can persist for at least 5 months after completion of the program. It further suggests that a focus on ADR does not lead to a "one and done" phenomenon. The limitations of this study were as follows: single-center setting, and lack of sessile polyp information/standardization.

Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers.

Clinical and neuropathological characteristics associated with G4C2 repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, are highly variable. To gain insight on the molecular basis for the heterogeneity among C9ORF72 mutation carriers, we evaluated associations between features of disease and levels of two abundantly expressed "c9RAN proteins" produced by repeat-associated non-ATG (RAN) translation of the expanded repeat. For these studies, we took a departure from traditional immunohistochemical approaches and instead employed immunoassays to quantitatively measure poly(GP) and poly(GA) levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [12 patients with ALS, 24 with frontotemporal lobar degeneration (FTLD) and 19 with FTLD with motor neuron disease (FTLD-MND)]. We additionally investigated associations between levels of poly(GP) or poly(GA) and cognitive impairment in 15 C9ORF72 ALS patients for whom neuropsychological data were available. Among the neuroanatomical regions investigated, poly(GP) levels were highest in the cerebellum. In this same region, associations between poly(GP) and both neuropathological and clinical features were detected. Specifically, cerebellar poly(GP) levels were significantly lower in patients with ALS compared to patients with FTLD or FTLD-MND. Furthermore, cerebellar poly(GP) associated with cognitive score in our cohort of 15 patients. In the cerebellum, poly(GA) levels similarly trended lower in the ALS subgroup compared to FTLD or FTLD-MND subgroups, but no association between cerebellar poly(GA) and cognitive score was detected. Both cerebellar poly(GP) and poly(GA) associated with C9ORF72 variant 3 mRNA expression, but not variant 1 expression, repeat size, disease onset, or survival after onset. Overall, these data indicate that cerebellar abnormalities, as evidenced by poly(GP) accumulation, associate with neuropathological and clinical phenotypes, in particular cognitive impairment, of C9ORF72 mutation carriers.