Causal Relationship Between Kidney Function and Cancer Risk: A Mendelian Randomization Study.

RATIONALE & OBJECTIVE: Patients treated with kidney replacement therapy experience a 1.5- to 2-fold increased risk of cancer and cancer mortality compared with the general population. Whether this excess risk extends to people with earlier stage chronic kidney disease and whether reduced kidney function is causally related to cancer is unclear. STUDY DESIGN: Two-sample Mendelian randomization (MR). SETTING & PARTICIPANTS: Genome-wide association study (GWAS) summary statistics for estimated glomerular filtration rate (eGFR) (n=567,460) and urinary albumin-creatine ratio (UACR) (n=127,865) from the CKDGen consortium and cancer outcomes from the UK Biobank (n = 407,329). EXPOSURE: eGFR and UACR. OUTCOME: Overall cancer incidence, cancer-related mortality and site-specific colorectal, lung, and urinary tract cancer incidence. ANALYTICAL APPROACH: Univariable and multivariable MR conducted for all outcomes. RESULTS: The mean eGFR and median UACR were 91.4mL/min/1.73m2 and 9.32mg/g, respectively, in the CKDGen, and 90.4mL/min/1.73m2 and 9.29mg/g, respectively, in the UK Biobank. There were 98,093 cases of cancer, 15,850 cases of cancer-related death, 6,664 colorectal, 3584 lung, and 3,271 urinary tract cancer cases, respectively. The genetic instruments for eGFR and UACR comprised 34 and 38 variants, respectively. Genetically predicted kidney function (eGFR and UACR) was not associated with overall cancer risk or cancer death. The association between genetically predicted eGFR and UACR and overall cancer incidence had an odds ratio of 0.88 ([95% CI, 0.40-1.97], P=0.8) and 0.90 ([95% CI, 0.78-1.04], P=0.2) respectively, using the inverse-variance weighted method. An adjusted generalized additive model for eGFR and cancer demonstrated evidence of nonlinearity. However, there was no evidence of a causal association between eGFR and cancer in a stratified MR. LIMITATIONS: To avoid overlapping samples a smaller GWAS for UACR was used, which reduced the strength of the instrument and may introduce population stratification. CONCLUSIONS: Our study did not show a causal association between kidney function, overall cancer incidence, and cancer-related death. PLAIN-LANGUAGE SUMMARY: Does reduced kidney function cause cancer? Patients with chronic kidney disease have been shown to have an increased risk of cancer and cancer-related death. However, it is not clear whether kidney disease is causally related to cancer or the association is due to other factors such as immune suppression and inflammation or a result of distortion of the analyses from unidentified variables (confounding). We used large, published genetic studies as well a database including 407,329 people in the United Kingdom in a series of Mendelian randomization analysis. Mendelian randomization uses the random assignment of genetic variants at birth to investigate causal relationships without confounding from measured and unmeasured confounders. We found that there is no evidence of a causal relationship between reduced kidney function and cancer.

Frailty and Associated Environmental Factors Only Have Small Effects on Age of Onset in Huntington's Disease.

BACKGROUND: Over one third of age of onset variation in Huntington's disease is unexplained by CAG repeat length. In Alzheimer's disease, frailty partly modulates the relationship between neuropathology and dementia. OBJECTIVE: We investigated whether a multi-domain frailty index, reflecting non-genetic factors in Huntington's disease, similarly modulates the relationship between CAG repeat length and age of onset. METHODS: We created a frailty index assessing comorbidities, substance abuse, polypharmacy, and education. We applied multiple linear regression models to 2,741 subjects with manifest Huntington's disease from the Enroll-HD cohort study, including 729 subjects with late-onset (post-60 years) disease, using frailty index or constituent item scores and CAG repeat length as independent variables. We used actual and "residual" ages of onset (difference between actual and CAG-based predicted onset) as dependent variables, the latter offsetting the increased time available to accumulate comorbidities in older subjects. RESULTS: Higher frailty index scores were associated with significantly lower residual ages of onset in the late-onset subgroup (p = 0.03), though the effect was small (R2 = 0.27 with frailty as a predictor vs. 0.26 without). Number of comorbidities was also associated with significantly lower residual ages of onset in the late-onset subgroup (p = 0.04). Drug abuse and smoking were associated with significantly earlier ages of onset in the whole cohort (p < 0.01, p = 0.02) and late-onset subgroup (p < 0.01, p = 0.03). CONCLUSIONS: The impact of non-genetic factors on age of onset, assessed using a frailty index or separately, in Huntington's disease is limited.

An Australian community jury to consider case-finding for dementia: Differences between informed community preferences and general practice guidelines.

BACKGROUND: Case-finding for dementia is practised by general practitioners (GPs) in Australia but without an awareness of community preferences. We explored the values and preferences of informed community members around case-finding for dementia in Australian general practice. DESIGN, SETTING AND PARTICIPANTS: A before and after, mixed-methods study in Gold Coast, Australia, with ten community members aged 50-70. INTERVENTION: A 2-day citizen/community jury. Participants were informed by experts about dementia, the potential harms and benefits of case-finding, and ethical considerations. PRIMARY AND SECONDARY OUTCOMES: We asked participants, "Should the health system encourage GPs to practice 'case-finding' of dementia in people older than 50?" Case-finding was defined as a GP initiating testing for dementia when the patient is unaware of symptoms. We also assessed changes in participant comprehension/knowledge, attitudes towards dementia and participants' own intentions to undergo case-finding for dementia if it were suggested. RESULTS: Participants voted unanimously against case-finding for dementia, citing a lack of effective treatments, potential for harm to patients and potential financial incentives. However, they recognized that case-finding was currently practised by Australian GPs and recommended specific changes to the guidelines. Participants increased their comprehension/knowledge of dementia, their attitude towards case-finding became less positive, and their intentions to be tested themselves decreased. CONCLUSION: Once informed, community jury participants did not agree case-finding for dementia should be conducted by GPs. Yet their personal intentions to accept case-finding varied. If case-finding for dementia is recommended in the guidelines, then shared decision making is essential.

Clinical Management of Neuropsychiatric Symptoms of Huntington Disease: Expert-Based Consensus Guidelines on Agitation, Anxiety, Apathy, Psychosis and Sleep Disorders.

BACKGROUND: In clinical practice, several strategies and pharmacological options are available to treat neuropsychiatric symptoms of Huntington disease (HD). However, there is currently insufficient data for evidence-based guidelines on the management of these common symptoms. OBJECTIVE: We aimed to develop expert-based recommendations regarding the management of agitation, anxiety, apathy, psychosis, and sleep disorders. METHODS: Guideline development was based on a modified Institute of Medicine guideline process that accounted for a lack of evidence base. An international committee of 11 multidisciplinary experts proposed a series of statements regarding the description and management of each symptom. Statement assessment and validation was performed using a web-based survey tool and 84 international HD experts (neurologists and psychiatrists) who assessed the statements and indicated their level of agreement. RESULTS: High-level agreement (≥85% experts strongly agreed or agreed) was reached for 107 of the 110 statements that have been incorporated into the expert-based clinical recommendations presented herein. CONCLUSIONS: Clinical statements to guide the routine management of agitation, anxiety, apathy, psychosis, and sleep disorders in HD have been developed. Although not specifically tested in the HD population, clinical experience has shown that most of the neuropsychiatric symptoms discussed, when considered in isolation are treatable using pharmacologic and non-pharmacologic strategies developed for use in other populations. However, the management of neuropsychiatric symptoms in HD can be complex because neuropsychiatric symptoms often co-exist and treatment decisions should be adapted to cover all symptoms while limiting polypharmacy.

Screening for Dementia in Primary Care: A Comparison of the GPCOG and the MMSE.

BACKGROUND/AIMS: The General Practitioner Assessment of Cognition (GPCOG) is a brief cognitive test. This study compared the GPCOG to the Mini-Mental State Examination (MMSE), the most widely used test, in terms of their ability to detect likely dementia in primary care. METHODS: General practitioners across three states in Australia recruited 2,028 elderly patients from the community. A research nurse administered the GPCOG and the MMSE, as well as the Cambridge Examination for Mental Disorders of the Elderly Cognitive Scale-Revised that we used to define likely dementia. RESULTS: Overall, the GPCOG and the MMSE were similarly effective at detecting likely dementia. The GPCOG, however, had a higher sensitivity than the MMSE when using published cutpoints. CONCLUSION: The GPCOG is an effective screening tool for dementia in primary care. It appears to be a viable alternative to the MMSE, whilst also requiring less time to administer.

Paclitaxel-induced neuropathy: potential association of MAPT and GSK3B genotypes.

BACKGROUND: Paclitaxel treatment produces dose-limiting peripheral neurotoxicity, which adversely affects treatment and long-term outcomes. In the present study, the contribution of genetic polymorphisms to paclitaxel-induced neurotoxicity were assessed in 21 patients, focusing on polymorphisms involved in the tau-microtubule pathway, an important target of paclitaxel involved in neurotoxicity development. METHODS: Polymorphisms in the microtubule-associated protein tau (MAPT) gene (haplotype 1 and rs242557 polymorphism) and the glycogen synthase kinase-3ß (GSK3ß) gene (rs6438552 polymorphism) were investigated. Neurotoxicity was assessed using neuropathy grading scales, neurophysiological studies and patient questionnaires. RESULTS: A significant relationship between the GSK-3B rs6438552 polymorphism and paclitaxel-induced neurotoxicity was evident. CONCLUSIONS: Polymorphisms in tau-associated genes may contribute to the development of paclitaxel-induced neurotoxicity, although larger series will be necessary to confirm these findings.

Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.

OBJECTIVE: Frontotemporal lobar degeneration (FTLD) is the most common cause of early-onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans-activating response element (TAR) DNA binding protein (TDP-43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD-MND pedigree with no mutations in known dementia genes. METHODS: A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation. RESULTS: We identified a nonpolymorphic mutation (c.672*51G>T) in the 3'-untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD-MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4-fold, corresponding with a significant 1.5-fold to 2-fold change in the SIGMAR1 transcript or Sigma-1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP-43 or FUS but not Sigma-1. Overexpression of SIGMAR1 shunted TDP-43 and FUS from the nucleus to the cytoplasm by 2.3-fold and 5.2-fold, respectively. Treatment of cells with Sigma-1 ligands significantly altered translocation of TDP-43 by up to 2-fold. INTERPRETATION: SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies.

Low serum progranulin predicts the presence of mutations: a prospective study.

Serum progranulin is decreased in frontotemporal dementia (FTD) patients with progranulin gene (PGRN) mutations. We investigate the utility of prospective serum screening as a surrogate diagnostic marker for progranulin mutations. A commercial ELISA was used to measure progranulin protein concentration in serum from 63 FTD patients and 32 normal controls, and DNA screening then performed. Four patients (2/17 behavioral variant, 2/8 corticobasal syndrome) had abnormally low progranulin levels with PGRN mutations confirmed on DNA testing. Surprisingly, elevated levels were found in 6/16 patients with progressive non-fluent aphasia, the significance of which is unclear. Serum testing is an accurate and cost effective means of predicting PGRN mutations.

Quantitative live imaging of cancer and normal cells treated with Kinesin-5 inhibitors indicates significant differences in phenotypic responses and cell fate.

Kinesin-5 inhibitors (K5I) are promising antimitotic cancer drug candidates. They cause prolonged mitotic arrest and death of cancer cells, but their full range of phenotypic effects in different cell types has been unclear. Using time-lapse microscopy of cancer and normal cell lines, we find that a novel K5I causes several different cancer and noncancer cell types to undergo prolonged arrest in monopolar mitosis. Subsequent events, however, differed greatly between cell types. Normal diploid cells mostly slipped from mitosis and arrested in tetraploid G(1), with little cell death. Several cancer cell lines died either during mitotic arrest or following slippage. Contrary to prevailing views, mitotic slippage was not required for death, and the duration of mitotic arrest correlated poorly with the probability of death in most cell lines. We also assayed drug reversibility and long-term responses after transient drug exposure in MCF7 breast cancer cells. Although many cells divided after drug washout during mitosis, this treatment resulted in lower survival compared with washout after spontaneous slippage likely due to chromosome segregation errors in the cells that divided. Our analysis shows that K5Is cause cancer-selective cell killing, provides important kinetic information for understanding clinical responses, and elucidates mechanisms of drug sensitivity versus resistance at the level of phenotype.

VBM signatures of abnormal eating behaviours in frontotemporal lobar degeneration.

The brain bases of specific human behaviours in health and disease are not well established. In this voxel-based morphometric (VBM) study we demonstrate neuroanatomical signatures of different abnormalities of eating behaviour (pathological sweet tooth and increased food consumption, or hyperphagia) in individuals with frontotemporal lobar degeneration (FTLD). Sixteen male patients with FTLD were assessed using the Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia and classified according to the presence or absence of abnormal eating behaviours. Volumetric brain magnetic resonance imaging was performed in all patients and in a group of nine healthy age-matched male controls and grey matter changes were assessed using an optimised VBM protocol. Compared with healthy controls, the FTLD group had a typical pattern of extensive bilateral grey matter loss predominantly involving the frontal and temporal lobes. Within the FTLD group, grey matter changes associated with different abnormal behaviours were assessed independently using a covariate-only model. The development of pathological sweet tooth was associated with grey matter loss in a distributed brain network including bilateral posterolateral orbitofrontal cortex (Brodmann areas 12/47) and right anterior insula. Hyperphagia was associated with more focal grey matter loss in anterolateral OFC bilaterally (Brodmann area 11). In accord with emerging evidence in humans and other species, our findings implicate distinct components of a multi-component brain network in the control of specific aspects of eating behaviour.

Treatment of opportunistic infections and lymphoma in the nervous system.

The advent of highly active antiretroviral therapy has affected many aspects of the management of AIDS-related opportunistic infections (OIs). Aspects of treating OIs of the brain, spinal cord, peripheral nerves and muscles are discussed, with emphasis on more recent developments in this area. Treatment for primary and metastatic central nervous system lymphoma is also reviewed.