Uncovering key clinical trial features influencing recruitment.

Background: Randomized clinical trials (RCT) are the foundation for medical advances, but participant recruitment remains a persistent barrier to their success. This retrospective data analysis aims to (1) identify clinical trial features associated with successful participant recruitment measured by accrual percentage and (2) compare the characteristics of the RCTs by assessing the most and least successful recruitment, which are indicated by varying thresholds of accrual percentage such as ≥ 90% vs ≤ 10%, ≥ 80% vs ≤ 20%, and ≥ 70% vs ≤ 30%. Methods: Data from the internal research registry at Columbia University Irving Medical Center and Aggregated Analysis of ClinicalTrials.gov were collected for 393 randomized interventional treatment studies closed to further enrollment. We compared two regularized linear regression and six tree-based machine learning models for accrual percentage (i.e., reported accrual to date divided by the target accrual) prediction. The outperforming model and Tree SHapley Additive exPlanations were used for feature importance analysis for participant recruitment. The identified features were compared between the two subgroups. Results: CatBoost regressor outperformed the others. Key features positively associated with recruitment success, as measured by accrual percentage, include government funding and compensation. Meanwhile, cancer research and non-conventional recruitment methods (e.g., websites) are negatively associated with recruitment success. Statistically significant subgroup differences (corrected p-value < .05) were found in 15 of the top 30 most important features. Conclusion: This multi-source retrospective study highlighted key features influencing RCT participant recruitment, offering actionable steps for improvement, including flexible recruitment infrastructure and appropriate participant compensation.

A data-driven approach to optimizing clinical study eligibility criteria.

OBJECTIVE: Feasible, safe, and inclusive eligibility criteria are crucial to successful clinical research recruitment. Existing expert-centered methods for eligibility criteria selection may not be representative of real-world populations. This paper presents a novel model called OPTEC (OPTimal Eligibility Criteria) based on the Multiple Attribute Decision Making method boosted by an efficient greedy algorithm. METHODS: It systematically identifies the optimal criteria combination for a given medical condition with the optimal tradeoff among feasibility, patient safety, and cohort diversity. The model offers flexibility in attribute configurations and generalizability to various clinical domains. The model was evaluated on two clinical domains (i.e., Alzheimer's disease and Neoplasm of pancreas) using two datasets (i.e., MIMIC-III dataset and NewYork-Presbyterian/Columbia University Irving Medical Center (NYP/CUIMC) database). RESULTS: We simulated the process of automatically optimizing eligibility criteria according to user-specified prioritization preferences and generated recommendations based on the top-ranked criteria combination accordingly (top 0.41-2.75%) with OPTEC. Harnessing the power of the model, we designed an interactive criteria recommendation system and conducted a case study with an experienced clinical researcher using the think-aloud protocol. CONCLUSIONS: The results demonstrated that OPTEC could be used to recommend feasible eligibility criteria combinations, and to provide actionable recommendations for clinical study designers to construct a feasible, safe, and diverse cohort definition during early study design.

Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers.

OBJECTIVE: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. METHODS: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. RESULTS: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36-60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = -2.35 to -1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = -2.14 to -1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = -1.80 to -1.18). INTERPRETATION: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424-435.

Prospective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial.

BACKGROUND: Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. METHODS: This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. RESULTS: OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. CONCLUSIONS: Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium.

The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed.

Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs.

BACKGROUND: Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). The advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified. RESULTS: We perform whole genome methyl-seq on diverse normal cells and tissues and three cancer types. After excluding imprinting, the data pinpoint 15,112 high-confidence ASM differentially methylated regions, of which 1838 contain SNPs in strong linkage disequilibrium or coinciding with GWAS peaks. ASM frequencies are increased in cancers versus matched normal tissues, due to widespread allele-specific hypomethylation and focal allele-specific hypermethylation in poised chromatin. Cancer cells show increased allele switching at ASM loci, but disruptive SNPs in specific classes of CTCF and transcription factor binding motifs are similarly correlated with ASM in cancer and non-cancer. Rare somatic mutations affecting these same motif classes track with de novo ASM. Allele-specific transcription factor binding from ChIP-seq is enriched among ASM loci, but most ASM differentially methylated regions lack such annotations, and some are found in otherwise uninformative "chromatin deserts." CONCLUSIONS: ASM is increased in cancers but occurs by a shared mechanism involving disruptive SNPs in CTCF and transcription factor binding sites in both normal and neoplastic cells. Dense ASM mapping in normal plus cancer samples reveals candidate rSNPs that are difficult to find by other approaches. Together with GWAS data, these rSNPs can nominate specific transcriptional pathways in susceptibility to autoimmune, cardiometabolic, neuropsychiatric, and neoplastic diseases.

Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls.

BACKGROUND: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. METHODS: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. RESULTS: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. CONCLUSIONS: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.

Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study.

PURPOSE: Recruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results. METHODS: The costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined. RESULTS: A total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from $579 to $1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample. CONCLUSIONS: Although all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research.

A comprehensive screening of copy number variability in dementia with Lewy bodies.

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.

Dietary Patterns, Physical Activity, Sleep, and Risk for Dementia and Cognitive Decline.

PURPOSE OF REVIEW: Diet, physical activity, and sleep are three major modifiable lifestyle factors. This selective review examines the evidence for strong and reliable associations between these three lifestyle factors and risk of dementia and cognitive decline, in an effort to assist clinicians with providing more informed answers to the common questions they face from patients. RECENT FINDINGS: Certain aspects of nutrition can decrease risk for dementia. Physical activity has also been associated with delayed or slower age-related cognitive decline. In addition, emerging evidence links sleep dysfunction and dementia, with amyloid deposition being a possible mediator. Data from further clinical trials are needed before more definitive conclusions can be drawn regarding the efficacy of these lifestyle interventions for lowering the risk of incident dementia and cognitive decline. Nevertheless, it is reasonable to make recommendations to our patients to adopt certain dietary changes and to engage in regular physical activity to improve cardiovascular risk factors for dementia. It is also reasonable to include questions on sleep during cognitive evaluations of the elderly, given the common co-occurrence of sleep dysfunction and cognitive impairment in the elderly population.

Genetic and Clinical Predictors of Deep Brain Stimulation in Young-Onset Parkinson's Disease.

OBJECTIVE: In a cohort of patients with young-onset Parkinson's disease (PD), the authors assessed (1) the prevalence of genetic mutations in those who enrolled in deep brain stimulation (DBS) programs compared with those who did not enroll DBS programs and (2) specific genetic and clinical predictors of DBS enrollment. METHODS: Subjects were participants from 3 sites (Columbia University, Rush University, and the University of Pennsylvania) in the Consortium on Risk for Early Onset Parkinson's Disease (CORE-PD) who had an age at onset < 51 years. The analyses presented here focus on glucocerebrosidase (GBA), leucine-rich repeat kinase 2 (LRRK2), and parkin (PRKN) mutation carriers. Mutation carrier status, demographic data, and disease characteristics in individuals who did and did not enroll in DBS were analyzed. The association between mutation status and DBS placement was assessed in logistic regression models. RESULTS: Patients who had PD with either GBA, LRRK2, or PRKN mutations were more common in the DBS group (n = 99) compared with the non-DBS group (n = 684; 26.5% vs. 16.8%, respectively; P = 0.02). In a multivariate logistic regression model, GBA mutation status (odds ratio, 2.1; 95% confidence interval, 1.0-4.3; P = 0.05) was associated with DBS surgery enrollment. However, when dyskinesia was included in the multivariate logistic regression model, dyskinesia had a strong association with DBS placement (odds ratio, 3.8; 95% confidence interval, 1.9-7.3; P < 0.0001), whereas the association between GBA mutation status and DBS placement did not persist (P = 0.25). CONCLUSIONS: DBS populations are enriched with genetic mutation carriers. The effect of genetic mutation carriers on DBS outcomes warrants further exploration.

Olfactory identification in LRRK2 G2019S mutation carriers: a relevant marker?

OBJECTIVE: Olfactory impairment is a potential marker for impending phenoconversion to Parkinson disease (PD) that may precede the development of disease by several years. Because of low specificity, it may be of greater predictive value in those with genetic mutations and its potential as a marker for developing LRRK2 PD should be evaluated. METHODS: We examined olfactory identification in 126 LRRK2 G2019S mutation carriers with PD, 125 mutation carriers not manifesting PD, 126 noncarriers with idiopathic PD, 106 noncarrier family members without PD, and 35 unrelated controls. We compared olfactory performance and performed mixture modeling to identify possible subgroups of olfactory performance in LRRK2 PD and nonmanifesting carriers. RESULTS: Adjusting for sex, age, cognitive score, site, and smoking history, LRRK2 PD had better olfactory scores compared to idiopathic PD (mean olfaction difference: -3.7, P < 0.001), and both LRRK2 PD and idiopathic PD had worse olfaction than controls (-12.8, -9.1, both P < 0.001). LRRK2 PD were less likely to be hyposmic than idiopathic PD (54.8% vs. 80.2%, P < 0.001). Nonmanifesting carriers and noncarrier family members did not differ. Mixture model analysis identified three classes in the LRRK2 PD and nonmanifesting carriers, suggesting that there are subgroups with poor olfactory identification in both LRRK2 PD and nonmanifesting carriers. INTERPRETATION: Therefore, olfactory identification deficit is less likely to be an obligate feature in LRRK2 PD than idiopathic PD, and while a relevant marker in some, a subset of carriers who eventually phenoconvert may proceed directly to PD without prior impaired olfaction.

Views of internists towards uses of PGD.

Preimplantation genetic diagnosis (PGD) is increasingly available, but how physicians view it is unclear. Internists are gatekeepers and sources of information, often treating disorders for which PGD is possible. This quantitative study surveyed 220 US internists, who were found to be divided. Many would recommend PGD for cystic fibrosis (CF; 33.7%), breast cancer (BRCA; 23.4%), familial adenomatous polyposis (FAP; 20.6%) and familial hypertrophic cardiomyopathy (19.9%), but few for social sex selection (5.2%); however, in each case, >50% were unsure. Of those surveyed, 4.9% have suggested PGD to patients. Only 7.1% felt qualified to answer patient questions about it. Internists who would refer for PGD had completed medical training less recently and, for CF, were more likely to have privately insured patients (P<0.033) and patients who reported genetic discrimination (P<0.013). Physicians more likely to refer for BRCA and FAP were less likely to have patients ask about genetic testing. This study suggests that internists often feel they have insufficient knowledge about it and may refer for PGD based on limited understanding. They view possible uses of PGD differently, partly reflecting varying ages of onset and disease treatability. These data have critical implications for training, research and practice. Preimplantation genetic diagnosis (PGD) allows embryos to be screened prior to transfer to a woman's womb for various genetic markers. This procedure raises complex medical, social, psychological and ethical issues, but how physicians view it is unclear. Internists are gatekeepers and sources of information, often treating disorders for which PGD use is possible. We surveyed 220 US internists, who were found to be divided: many would recommend PGD for cystic fibrosis (CF; 33.7%), breast cancer (BRCA; 23.4%), familial adenomatous polyposis (FAP; 20.6%), and familial hypertrophic cardiomyopathy (FHC; 19.9%) and a few for sex selection (5.2%); but in each case, >50% were unsure. Of those surveyed, 4.9% have suggested PGD to patients. Only 7.1% felt qualified to answer patient questions. Internists who would refer for PGD completed medical training less recently and, for CF, were more likely to have privately insured patients and patients who reported genetic discrimination. Physicians more likely to refer for BRCA and FAP were less likely to have patients ask about genetic testing. This quantitative study suggests that internists often feel they have insufficient knowledge and may refer for PGD based on limited understanding. They view possible uses of PGD differently, partly reflecting varying ages of onset and disease treatability. Internists should be made aware of the potential benefit of PGD, but also be taught to refer patients, when appropriate, to clinical geneticists who could then refer the patient to an IVF/PGD team. These data thus have critical implications for training, research and practice.

Attitudes and practices among internists concerning genetic testing.

Many questions remain concerning whether, when, and how physicians order genetic tests, and what factors are involved in their decisions. We surveyed 220 internists from two academic medical centers about their utilization of genetic testing. Rates of genetic utilizations varied widely by disease. Respondents were most likely to have ordered tests for Factor V Leiden (16.8 %), followed by Breast/Ovarian Cancer (15.0 %). In the past 6 months, 65 % had counseled patients on genetic issues, 44 % had ordered genetic tests, 38.5 % had referred patients to a genetic counselor or geneticist, and 27.5 % had received ads from commercial labs for genetic testing. Only 4.5 % had tried to hide or disguise genetic information, and <2 % have had patients report genetic discrimination. Only 53.4 % knew of a geneticist/genetic counselor to whom to refer patients. Most rated their knowledge as very/somewhat poor concerning genetics (73.7 %) and guidelines for genetic testing (87.1 %). Most felt needs for more training on when to order tests (79 %), and how to counsel patients (82 %), interpret results (77.3 %), and maintain privacy (80.6 %). Physicians were more likely to have ordered a genetic test if patients inquired about genetic testing (p < .001), and if physicians had a geneticist/genetic counselor to whom to refer patients (p < .002), had referred patients to a geneticist/genetic counselor in the past 6 months, had more comfort counseling patients about testing (p < .019), counseled patients about genetics, larger practices (p < .032), fewer African-American patients (p < .027), and patients who had reported genetic discrimination (p < .044). In a multiple logistic regression, ordering a genetic test was associated with patients inquiring about testing, having referred patients to a geneticist/genetic counselor and knowing how to order tests. These data suggest that physicians recognize their knowledge deficits, and are interested in training. These findings have important implications for future medical practice, research, and education.

Creation of an open-access, mutation-defined fibroblast resource for neurological disease research.

Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.

Lack of association between cancer history and PARKIN genotype: a family based study in PARKIN/Parkinson's families.

A number of publications have attributed a tumor suppressive (TS) function to PARKIN, a gene associated with recessive familial early onset Parkinson's disease (EOPD). Discoveries of PARKIN deletions and point mutations in tumors, functional studies, and data from mouse models have been presented to support the hypothesis. We have asked whether PARKIN mutations are associated with history of cancer in humans. We interviewed 431 participants who were screened for PARKIN mutations, including 149 EOPD cases and their family members, who were unaware of mutation status. We found no significant difference in self-reported history of cancer among carriers of one or two PARKIN mutations and noncarriers, odds ratio 0.75 (95% confidence interval 0.27-1.83). In particular, no increase in cancer history was seen among homozygous and compound heterozygous mutation carriers compared to noncarriers. Therefore, we hypothesize that published studies attributing TS capability to PARKIN merit further exploration and we present a reevaluation of these data with respect to patterns of mutation frequencies in normal and cancer cells. We conclude that although Parkin may exert a suppressive effect in mice, further studies are required prior to assigning a TS function to PARKIN in humans.

A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci.

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.

Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals.

Despite effective and widely available suppressive anti-HIV therapy, the prevalence of mild neurocognitive dysfunction continues to increase. HIV-associated neurocognitive disorder (HAND) is a multifactorial disease with sustained central nervous system inflammation and immune activation as prominent features. Inflammatory macrophages, HIV-infected and uninfected, play a central role in the development of HIV dementia. There is a critical need to identify biomarkers and to better understand the molecular mechanisms leading to cognitive dysfunction in HAND. In this regard, we identified through a subtractive hybridization strategy osteopontin (OPN, SPP1, gene) an inflammatory marker, as an upregulated gene in HIV-infected primary human monocyte-derived macrophages. Knockdown of OPN in primary macrophages resulted in a threefold decrease in HIV-1 replication. Ectopic expression of OPN in the TZM-bl cell line significantly enhanced HIV infectivity and replication. A significant increase in the degradation of the NF-κB inhibitor, IκBα and an increase in the nuclear-to-cytoplasmic ratio of NF-κB were found in HIV-infected cells expressing OPN compared to controls. Moreover, mutation of the NF-κB binding domain in the HIV-LTR abrogated enhanced promoter activity stimulated by OPN. Interestingly, compared to cerebrospinal fluid from normal and multiple sclerosis controls, OPN levels were significantly higher in HIV-infected individuals both with and without neurocognitive disorder. OPN levels were highest in HIV-infected individuals with moderate to severe cognitive impairment. Moreover, OPN was significantly elevated in brain tissue from HIV-infected individuals with cognitive disorder versus those without impairment. Collectively, these data suggest that OPN stimulates HIV-1 replication and that high levels of OPN are present in the CNS compartment of HIV-infected individuals, reflecting ongoing inflammatory processes at this site despite anti-HIV therapy.

A screening assessment of cognitive impairment in patients with ALS.

We wished to determine whether a screening test battery for cognitive impairment can be given practicably in a busy multidisciplinary ALS clinic, and to assess initial test performance in a sequentially drawn ALS population. We administered a word generation task (letter fluency), the Frontal Behavioral Inventory (FBI), and the Beck Depression Inventory (BDI) to 49 ALS patients and their caregivers during a visit to our ALS clinic. We also computed Clinical Dementia Rating (CDR) scale and ALS Functional Rating Scale (ALSFRS-R) scores for patients. Pearson correlation coefficients and regression analyses assessed associations between outcome measures. The test battery took 30 min to administer. Word generation was associated with the FBI score (r = -0.36, p = 0.01), and time to ALS diagnosis (p = 0.01). Caregiver depressive symptoms (BDI) correlated with the FBI (r = 0.40, p = 0.005) and motor severity (r = -0.47, p<0.01) in patients. CDR scores were associated with behavioral abnormalities and lower ALSFRS-R scores. We concluded that a screen of cognition could be administered during multidisciplinary ALS clinics. Frontostriatal cognitive impairment may be associated with behavioral syndromes and more rapid forms of ALS. Behavioral and motor impairment is associated with depressive symptoms in caregivers. Studies with formal neuropsychological tests are needed to determine the sensitivity and specificity of the screen in ALS.