Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC), mostly developed in fibrotic/cirrhotic liver, exhibits relatively low responsiveness to immune checkpoint blockade (ICB) therapy. As myeloid-derived suppressor cell (MDSC) is pivotal for immunosuppression, we investigated its role and regulation in the fibrotic microenvironment with an aim of developing mechanism-based combination immunotherapy. DESIGN: Functional significance of MDSCs was evaluated by flow cytometry using two orthotopic HCC models in fibrotic liver setting via carbon tetrachloride or high-fat high-carbohydrate diet and verified by clinical specimens. Mechanistic studies were conducted in human hepatic stellate cell (HSC)-peripheral blood mononuclear cell culture systems and fibrotic-HCC patient-derived MDSCs. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and a clinically trialled BET bromodomain inhibitor i-BET762 was determined. RESULTS: Accumulation of monocytic MDSCs (M-MDSCs), but not polymorphonuclear MDSCs, in fibrotic livers significantly correlated with reduced tumour-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumour-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumour phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signalling to trigger enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitor abrogated HSC-M-MDSC crosstalk to prevent HCC growth. Concomitant with patient-derived M-MDSC suppression by i-BET762, combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumour eradication and prolonged survival in the fibrotic-HCC mouse model. CONCLUSION: Our results signify how non-tumour-intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy.

Genetic variation in ABCB5 associates with risk of hepatocellular carcinoma.

Expression of ATP-binding cassette B5 (ABCB5) has been demonstrated to confer chemoresistance, enhance cancer stem cell properties and associate with poor prognosis in hepatocellular carcinoma (HCC). The aim of this study was to evaluate the genetic variations of ABCB5 in HCC patients with reference to healthy individuals and the clinicopathological significance. A pilot study has examined 20 out of 300 pairs HCC and paralleled blood samples using conventional sequencing method to cover all exons and exon/intron regions to investigate whether there will be novel variant sequence and mutation event. A total of 300 HCC and 300 healthy blood DNA samples were then examined by Sequenom MassARRAY genotyping and pyrosequencing for 38 SNP and 1 INDEL in ABCB5. Five novel SNPs were identified in ABCB5. Comparison of DNA from blood samples of HCC and healthy demonstrated that ABCB5 SNPs rs75494098, rs4721940 and rs10254317 were associated with HCC risk. Specific ABCB5 variants were associated with aggressive HCC features. SNP rs17143212 was significantly associated with ABCB5 expression level. Nonetheless, the paralleled blood and tumour DNA sequences from HCC patients indicated that ABCB5 mutation in tumours was not common and corroborated the TCGA data sets. In conclusion, ABCB5 genetic variants had significant association with HCC risk and aggressive tumour properties.

Health care costs of depression in patients diagnosed with cancer.

OBJECTIVE: Depression is common among patients diagnosed with cancer. Patients with cancer and depression use more health care services compared with nondepressed cancer patients. The current study seeks to estimate the added cost of depression in cancer patients in the first year after cancer diagnosis. METHODS: Health care charges were obtained for 2051 depressed and 11 182 nondepressed patients with an International Classification of Diseases, Ninth Revision, diagnosis of cancer in the 2014 calendar year from the University of California San Diego Healthcare System. The annual health care charges for cancer patients with and without depression were analyzed using generalized linear models with a log-link function and gamma distribution, covarying for age, sex, race/ethnicity, comorbid diseases, and presence of metastatic disease. Total cost data were broken down into several categories including ambulatory care, emergency department visits, and hospital visits. RESULTS: Depressed cancer patients had total annual health care charges that were 113% higher than nondepressed cancer patients (B = 0.76; P < .001). The estimated mean charges for depressed patients were $235 337 compared with $110 650 for nondepressed patients. Depressed cancer patients incurred greater charges than nondepressed patients in ambulatory care (B = 0.70; P < .001), emergency department charges (B = 0.31; P < .001), and hospital charges (B = 0.39; P < .001). CONCLUSIONS: Depressed cancer patients incur significantly higher health care charges across multiple cost categories including ambulatory care, emergency department visits, and hospital visits. Future research should investigate if interventions for detecting and treating depression are effective for reducing health care use and costs in cancer patients.

The Effects of Mechanical and Thermal Stimuli on Local Field Potentials and Single Unit Activity in Parkinson's Disease Patients.

BACKGROUND: Chronic pain is a major, debilitating symptom of Parkinson's disease (PD). Although, deep brain stimulation (DBS) has been shown to improve pain outcomes, the mechanisms underlying this phenomenon are unclear. Microelectrode recording allows us to measure both local field potentials (LFPs) and single neuronal unit activity (SUA). OBJECTIVE: In this study, we examined how single unit and LFP oscillatory activity in the basal ganglia are impacted by mechanical and thermal sensory stimuli and explored their role in pain modulation. METHODS: We assessed changes in LFPs and SUAs in the subthalamic nucleus (STN), globus pallidus interna (Gpi), and globus pallidus externa (Gpe) following exposure with mechanical or thermal stimuli. Sensory thresholds were determined pre-operatively using quantitative sensory testing. Based on these data, patients were exposed to innocuous and noxious mechanical, pressure, and thermal stimuli at individualized thresholds. RESULTS: In the STN, LFP alpha oscillatory activity and SUA increased in response to innocuous mechanical stimuli; SUA further increased in response to noxious mechanical, noxious pressure, and noxious thermal stimuli (p < 0.05). In the Gpe, LFP low betaactivity and SUA increased with noxious thermal stimuli; SUA also increased in response to innocuous thermal stimuli (p < 0.05). In the Gpi, innocuous thermal stimuli increased LFP gammaactivity; noxious pressure stimuli decreased low betaactivity; SUA increased in response to noxious thermal stimuli (p < 0.05). DISCUSSION: Our study is the first to demonstrate that mechanical and thermal stimuli alter basal ganglia LFPs and SUAs in PD. While STN SUA increases nearly uniformly to all sensory stimuli, SUA in the pallidal nuclei respond solely to thermal stimuli. Similarly, thermal stimuli yield increases in pallidal LFP activity, but not STN activity. We speculate that DBS may provide analgesia through suppression of stimuli-specific changes in basal ganglia activity, supporting a role for these nuclei in sensory and pain processing circuits.

Rates and risk factors associated with the progression of HIV to AIDS among HIV patients from Zhejiang, China between 2008 and 2012.

OBJECTIVES: The objective of this study was to determine the rate of acquired immune deficiency syndrome (AIDS) in Zhejiang province and to identify specific factors associated with progression of this disease. METHODS: This study utilized a retrospective cohort to identify the specific factors involved in the progression of human immunodeficiency virus (HIV) to AIDS. We collected data of patients existing in care between 2008 and 2012 from the national surveillance system databases. We performed our analyses using a multivariate Cox proportional hazards model. RESULTS: This study included 9216 HIV-positive patients (75.6 % male), which yielded 12,452 person-years (py) of follow-up-data. The AIDS progression rates were 33.9 % (2008), 33.6 % (2009), 38.1 % (2010), 30.6 % (2011) and 25.9 % (2012). We observed a significant reduction in the rate of progression Of HIV to AIDS post-2010 (Pearson χ(2) = 4341.9, P < 0.001). The cumulative AIDS progression incidence rates were 33.4, 35.4, 36.4, 37.0 and 37.04 per 100 py in 1 each of the 5 years of follow-up. This study found that age was an independent risk factor for the progression of HIV to AIDS. Compared with patients infected with HIV by homosexual transmission, patients infected with HIV by heterosexuals transmission or blood transfusion had a reduced hazard ratio (HR) for progression to AIDS (heterosexual transmission: HR = 0.695, 0.524, P = 0.007; blood transfusion: HR = 0.524, P = 0.015). Diagnosed with HIV from 2011 to 2012 and having a higher CD4+ cell count (350-500 cells/mm(3); or >500 cells/mm(3)) at baseline were independently associated with lower rates of HIV progression to AIDS [HR = 0.382, 0.380, 0.187, P < 0.001]. Patients with a CD+ T-cell count of 200-350 cells/mm(3) or greater than 350 cells/mm(3) were less likely to develop AIDS following HIV diagnosis than were those patients without HAART treatment. CONCLUSION: This study found a high progression rate from HIV to AIDS in HIV patients residing within Zhejiang province from 2008 to 2010. This rate decreased after 2010, which coincided with the new criteria for HAART treatment, which likely contributed to the observed reduction in the rate of progression. Initiation of HAART with higher CD4+ T-cell count may reduce rate of AIDS progression. Based on our results, we conclude that efficient strategies for HIV screening, as well as early diagnosis and treatment are necessary to reduce the progression of HIV to AIDS.

Measuring fragmentation of ambulatory care in a tripartite healthcare system.

BACKGROUND: Hong Kong has a tripartite healthcare system, where western medicine provided in both public and private sectors coexist with Chinese medicine practice. The purpose of this study is to measure fragmentation of ambulatory care experienced by the non-institutionalized population aged 15 and over in such a tripartite system, thus shed light on the ongoing primary care reform. METHODS: This is a cross-sectional secondary data analysis using the Thematic Household Survey, which was conducted by the Hong Kong Census and Statistics Department during November 2009 to February 2010 to collect territory-wide health-related information. Among 18,226 individuals with two or more ambulatory visits during the past 12 months before interview, we grouped each visit into one of the three care segments-public western, private western and Chinese medicine. Two individual-level measures were used to quantify longitudinal fragmentation of care across segments over the one-year period: Most Frequent Provider Continuity Index (MFPC) and Fragmentation of Care Index (FCI). Both are analyzed for distribution and subgroup comparison. A Tobit model was used to further examine the determinants of fragmentation. RESULTS: More than a quarter of individuals sought care in two or all three segments, with an average MFPC of 65% and FCI of 0.528. Being older, female, married, unemployed, uninsured, or born in mainland China, with lower education, lower income, higher number of chronic conditions or poorer health were found to have experienced higher fragmentation of care. We also found that, fragmentation of care increased with the total number of ambulatory care visits and it varied significantly depending on what segment the individual chose to visit most frequently-those chose private western clinics had lower FCI, compared with those chose public western or Chinese medicine as the most frequently visited segment. CONCLUSIONS: Even measured at healthcare segment level, people in Hong Kong experienced modest fragmentation of care. Individuals' health beliefs-as a result of the persistent habitual tendency and latitude incentivized by the system-may be behind the fragmented care we saw. Efforts are needed to alter health beliefs, targeting subgroups of vulnerable population, and create environments that promote better coordinated primary care.

Protocol for isolating human BCAM-positive corneal progenitor cells by flow cytometry and cell sorting.

BCAM-positive basal limbal epithelial cells are an early transit-amplifying cell population (TAC) capable of holoclone formation and corneal epithelial differentiation. Here, we present a protocol for isolating BCAM-positive cells from human donor corneas by flow cytometry and cell sorting. We describe steps for cell dissection and dissociation, antibody staining, and flow cytometry. We then detail procedures for culturing the purified BCAM-positive and BCAM-negative cells for holoclone and cell sheet formation assays to study the factors that regulate corneal regeneration. For complete details on the use and execution of this protocol, please refer to Sasamoto et al.1.

Hyperbaric oxygen for idiopathic sudden sensorineural hearing loss and tinnitus.

BACKGROUND: This is an update of a Cochrane Review first published in The Cochrane Library in Issue 1, 2005 and previously updated in 2007 and 2009.Idiopathic sudden sensorineural hearing loss (ISSHL) is common and has a significant effect on quality of life. Hyperbaric oxygen therapy (HBOT) may improve oxygen supply to the inner ear and result in an improvement in hearing. OBJECTIVES: To assess the benefits and harms of HBOT for treating ISSHL and/or tinnitus. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; Database of Randomised Trials in Hyperbaric Medicine (DORCTHIM); CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 2 May 2012, following previous searches in 2009, 2007 and 2004. SELECTION CRITERIA: Randomised studies comparing the effect on ISSHL and tinnitus of HBOT and alternative therapies. DATA COLLECTION AND ANALYSIS: Three authors evaluated the quality of trials using the 'Risk of bias' tool and extracted data from the included trials. MAIN RESULTS: Seven trials contributed to this review (392 participants). The studies were small and of generally poor quality. Pooled data from two trials did not show any significant improvement in the chance of a 50% increase in hearing threshold on pure-tone average with HBOT (risk ratio (RR) with HBOT 1.53, 95% confidence interval (CI) 0.85 to 2.78, P = 0.16), but did show a significantly increased chance of a 25% increase in pure-tone average (RR 1.39, 95% CI 1.05 to 1.84, P = 0.02). There was a 22% greater chance of improvement with HBOT, and the number needed to treat (NNT) to achieve one extra good outcome was 5 (95% CI 3 to 20). There was also an absolute improvement in average pure-tone audiometric threshold following HBOT (mean difference (MD) 15.6 dB greater with HBOT, 95% CI 1.5 to 29.8, P = 0.03). The significance of any improvement in tinnitus could not be assessed.There were no significant improvements in hearing or tinnitus reported for chronic presentation (six months) of ISSHL and/or tinnitus. AUTHORS' CONCLUSIONS: For people with acute ISSHL, the application of HBOT significantly improved hearing, but the clinical significance remains unclear. We could not assess the effect of HBOT on tinnitus by pooled analysis. In view of the modest number of patients, methodological shortcomings and poor reporting, this result should be interpreted cautiously. An appropriately powered trial is justified to define those patients (if any) who can be expected to derive most benefit from HBOT.There is no evidence of a beneficial effect of HBOT on chronic ISSHL or tinnitus and we do not recommend the use of HBOT for this purpose.

Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver.

Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8+ T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.

Cell cycle-related kinase reprograms the liver immune microenvironment to promote cancer metastasis.

The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types. Although a role for cancer cell invasion programs has been well characterized, whether and how liver-intrinsic factors drive metastatic spread is incompletely understood. Here, we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase (CCRK) signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment. Using an inducible liver-specific transgenic model, we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer (CRC) metastasis to the liver, which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and lacking natural killer T (NKT) cells. Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7% (metastatic tumor weights) in the melanoma and CRC models, respectively. Mechanistically, CCRK activated nuclear factor-kappa B (NF-κB) signaling to increase the PMN-MDSC-trafficking chemokine C-X-C motif ligand 1 (CXCL1), which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice. Accordingly, CRC liver metastasis patients exhibited hyperactivation of hepatic CCRK/NF-κB/CXCL1 signaling, which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors. In summary, this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance. Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.

Plasma DNA End-Motif Profiling as a Fragmentomic Marker in Cancer, Pregnancy, and Transplantation.

Plasma DNA fragmentomics is an emerging area of research covering plasma DNA sizes, end points, and nucleosome footprints. In the present study, we found a significant increase in the diversity of plasma DNA end motifs in patients with hepatocellular carcinoma (HCC). Compared with patients without HCC, patients with HCC showed a preferential pattern of 4-mer end motifs. In particular, the abundance of plasma DNA motif CCCA was much lower in patients with HCC than in subjects without HCC. The aberrant end motifs were also observed in patients with other cancer types, including colorectal cancer, lung cancer, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma. We further observed that the profile of plasma DNA end motifs originating from the same organ, such as the liver, placenta, and hematopoietic cells, generally clustered together. The profile of end motifs may therefore serve as a class of biomarkers for liquid biopsy in oncology, noninvasive prenatal testing, and transplantation monitoring. SIGNIFICANCE: Plasma DNA molecules originating from the liver, HCC and other cancers, placenta, and hematopoietic cells each harbor a set of characteristic plasma DNA end motifs. Such markers carry tissue-of-origin information and represent a new class of biomarkers in the nascent field of fragmentomics.This article is highlighted in the In This Issue feature, p. 627.

Presence of donor-derived DNA and cells in the urine of sex-mismatched hematopoietic stem cell transplant recipients: implication for the transrenal hypothesis.

BACKGROUND: The term "transrenal DNA" was coined in 2000 to signify that DNA in urine may come from the passage of plasma DNA through the kidney barrier. Although DNA in the urine has the potential to provide a completely noninvasive source of nucleic acids for molecular diagnosis, its existence remains controversial. METHODS: We obtained blood and urine samples from 22 hematopoietic stem cell transplant (HSCT) recipients and used fluorescence in situ hybridization, PCR for short tandem repeats, mass spectrometry, quantitative PCR, and immunofluorescence detection to study donor-derived DNA in the urine. RESULTS: All HSCT recipients exhibited high amounts of donor-derived DNA in buffy coat and plasma samples. Male donor-derived DNA was detected in supernatants of urine samples from all 5 female sex-mismatched HSCT recipients. Surprisingly, the amount of DNA in urine supernatants was not correlated with the plasma value. Moreover, cell-free urine supernatants contained DNA fragments >350 bp that were absent in plasma. Donor-derived polymorphs were detected in urine by fluorescence in situ hybridization. Coincidentally, donor-derived cytokeratin-producing epithelial cells were discovered in urine samples from 3 of 10 sex-mismatched HSCT recipients as long as 14.2 years after transplantation. CONCLUSIONS: This report is the first to demonstrate the presence of donor-derived DNA in the urine of HSCT recipients; however, we show that much of this DNA originates from donor-derived cells, rather than from the transrenal passage of cell-free plasma DNA. Our discovery of donor-derived cytokeratin-producing epithelial cells raises interesting biological and therapeutic implications, e.g., the capacity of marrow stem cells to serve as an extrarenal source for renal tubule regeneration.

Effect of low-frequency deep brain stimulation on sensory thresholds in Parkinson's disease.

OBJECTIVE Chronic pain is a major distressing symptom of Parkinson's disease (PD) that is often undertreated. Subthalamic nucleus (STN) deep brain stimulation (DBS) delivers high-frequency stimulation (HFS) to patients with PD and has been effective in pain relief in a subset of these patients. However, up to 74% of patients develop new pain concerns while receiving STN DBS. Here the authors explore whether altering the frequency of STN DBS changes pain perception as measured through quantitative sensory testing (QST). METHODS Using QST, the authors measured thermal and mechanical detection and pain thresholds in 19 patients undergoing DBS via HFS, low-frequency stimulation (LFS), and off conditions in a randomized order. Testing was performed in the region of the body with the most pain and in the lower back in patients without chronic pain. RESULTS In the patients with chronic pain, LFS significantly reduced heat detection thresholds as compared with thresholds following HFS (p = 0.029) and in the off state (p = 0.010). Moreover, LFS resulted in increased detection thresholds for mechanical pressure (p = 0.020) and vibration (p = 0.040) compared with these thresholds following HFS. Neither LFS nor HFS led to changes in other mechanical thresholds. In patients without chronic pain, LFS significantly increased mechanical pain thresholds in response to the 40-g pinprick compared with thresholds following HFS (p = 0.032). CONCLUSIONS Recent literature has suggested that STN LFS can be useful in treating nonmotor symptoms of PD. Here the authors demonstrated that LFS modulates thermal and mechanical detection to a greater extent than HFS. Low-frequency stimulation is an innovative means of modulating chronic pain in PD patients receiving STN DBS. The authors suggest that STN LFS may be a future option to consider when treating Parkinson's patients in whom pain remains the predominant complaint.

Secreted PDZD2 exerts concentration-dependent effects on the proliferation of INS-1E cells.

PDZD2 (PDZ domain containing 2) is a multi-PDZ protein expressed in pancreas and many other tissues. PDZD2 shows extensive homology to pro-interleukin-16 (pro-IL-16) and is localized mainly to the endoplasmic reticulum. We have recently demonstrated that PDZD2, like pro-IL-16, is proteolytically cleaved at its C-terminus to generate a secreted protein, sPDZD2 (for secreted PDZD2). To understand the possible functional role of PDZD2 in pancreas, we investigated the cellular distribution of PDZD2 in adult pancreas using an antiserum that recognizes both the full-length and secreted forms of PDZD2. Immunohistochemical analysis revealed a strong expression of PDZD2 in pancreatic islet beta cells but not alpha cells. Consistent with the beta-cell-enriched expression of PDZD2, immunoblot analysis indicated expression of both full-length PDZD2 and sPDZD2 in the insulinoma cell line INS-1E. A recombinant sPDZD2 protein was synthesized for study of its functional effect on INS-1E cells. In culture media with limiting serum, co-incubation with sPDZD2 stimulated the proliferation of INS-1E cells. The mitogenic effect of sPDZD2 was concentration-dependent, and was associated with a slight inhibition of the insulin promoter activity at high sPDZD2 concentrations. As a potential mitogen of beta-like cells, sPDZD2 may be useful for the optimization of beta-cell growth and differentiation in vitro.

Assessing Fluctuating Cognition in Dementia Diagnosis: Interrater Reliability of the Clinician Assessment of Fluctuation.

Fluctuating cognition (FC) is a core feature of dementia with Lewy bodies (DLB) but is challenging to assess. This study assessed the reliability and validity of the Clinician Assessment of Fluctuation (CAF), which assesses FC in patients with dementia. Interrater agreement of CAF outcomes (FC present and FC severe) was evaluated between physicians and nonphysicians in 141 patients with Alzheimer's disease (AD) or DLB. Frequency of CAF outcomes by clinical and neuropathological diagnosis was examined. We found that interrater reliability was fair on FC present and almost perfect on FC severe, and both outcomes were higher in patients with clinical DLB than with clinical AD and were qualitatively more often endorsed in cases with neuropathological evidence of Lewy bodies. We conclude that the CAF is a reliable measure of FC and can be valuable in differential dementia diagnosis.

Subjective word-finding difficulty reduces engagement in social leisure activities in Alzheimer's disease.

OBJECTIVES: To assess the influence of subjective word-finding difficulty on degree of engagement in social leisure activities among individuals with Alzheimer's disease (AD). DESIGN: Analysis of data collected from the second cohort of the Multicenter Study of Predictors of Disease Course in Alzheimer's disease. SETTING: Four study sites in the United States and France. PARTICIPANTS: Individuals diagnosed with mild to moderate AD (N = 236). MEASUREMENTS: On separate questionnaires, participants were asked to 1) report whether they had trouble finding the right word when speaking (subjective word-finding difficulty) and 2) rate their frequency and enjoyment of social and nonsocial leisure activities. Objective language measures included object naming and verbal fluency. Measures of dependence, depression, cognitive status, age, sex, and education were also included as covariates in regression analyses. RESULTS: Fifty-two percent of the sample reported word-finding difficulty, and subjective complaints were correlated with poorer verbal fluency scores. Subjective word-finding difficulty was selectively related to social but not nonsocial activity measures. Endorsers of word-finding difficulty reported less frequency and enjoyment of social leisure activities, controlling for effects of covariates and objective word-finding ability. In contrast, lower engagement in nonsocial activities was associated with older age and higher depression scores but not with word-finding complaints. Caregivers' reports of study participants' activities corroborated these results. CONCLUSION: Individuals with AD who are aware of increasing word-finding failures are less likely to participate in and enjoy socially oriented leisure activities. This finding may have significant implications for clinical and health outcomes in AD. Failure to evaluate subjective language complaints could result in social withdrawal symptoms, threatening the individual's quality of life and increasing caregiver burden. Reduced social interaction may ultimately exacerbate language symptoms over time.