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.

Apathy and Depression in Huntington's Disease: Distinct Longitudinal Trajectories and Clinical Correlates.

OBJECTIVE: Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease resulting in motor disturbances, dementia, and psychiatric symptoms. Apathy is a common manifestation and rated as one of the most impactful by patients and caregivers. It can often be difficult to distinguish from depression because of shared features and frequent overlap. This study examined the longitudinal trajectories and clinical correlates of apathy and depression. METHODS: Data were drawn from the Cooperative Huntington Observational Research Trial, a prospective, multicenter observational study that recruited 1,082 patients with HD. Measures of cognition, function, neuropsychiatric symptoms, motor function, and medication use were completed annually over 5 years. RESULTS: Overall, 423 patients (39%) showed evidence of apathy at study baseline, and both the prevalence and overall severity of apathy increased over time. Depression, by contrast, affected a similar proportion at baseline, although levels remained relatively stable over the study. Apathy was associated with worse cognition, function, neuropsychiatric symptoms, and motor symptoms. Depression was associated with worse neuropsychiatric symptoms, suicidal ideation, and independence but not other outcomes after control for other variables. CONCLUSIONS: Apathy in HD increased over time and was associated with worse clinical outcomes. These associations were independent of depression and other clinical variables. The findings highlight the need to distinguish between apathy and depression given their distinct implications for prognosis and management.

CNS cell type-specific gene profiling of P301S tau transgenic mice identifies genes dysregulated by progressive tau accumulation.

The microtubule-associated protein tau undergoes aberrant modification resulting in insoluble brain deposits in various neurodegenerative diseases, including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal degeneration. Tau aggregates can form in different cell types of the central nervous system (CNS) but are most prevalent in neurons. We have previously recapitulated aspects of human FTD in mouse models by overexpressing mutant human tau in CNS neurons, including a P301S tau variant in TAU58/2 mice, characterized by early-onset and progressive behavioral deficits and FTD-like neuropathology. The molecular mechanisms underlying the functional deficits of TAU58/2 mice remain mostly elusive. Here, we employed functional genomics (i.e. RNAseq) to determine differentially expressed genes in young and aged TAU58/2 mice to identify alterations in cellular processes that may contribute to neuropathy. We identified genes in cortical brain samples differentially regulated between young and old TAU58/2 mice relative to nontransgenic littermates and by comparative analysis with a dataset of CNS cell type-specific genes expressed in nontransgenic mice. Most differentially-regulated genes had known or putative roles in neurons and included presynaptic and excitatory genes. Specifically, we observed changes in presynaptic factors, glutamatergic signaling, and protein scaffolding. Moreover, in the aged mice, expression levels of several genes whose expression was annotated to occur in other brain cell types were altered. Immunoblotting and immunostaining of brain samples from the TAU58/2 mice confirmed altered expression and localization of identified and network-linked proteins. Our results have revealed genes dysregulated by progressive tau accumulation in an FTD mouse model.

The complex relationship between genotype, pathology and phenotype in familial dementia.

Causative genes involved in familial forms of dementias, including Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB), as well as amyotrophic lateral sclerosis and prion diseases where dementia is present as a significant clinical feature, are associated with distinct proteinopathies. This review summarizes the relationship between known genetic determinants of these dementia syndromes and variations in key neuropathological proteins in terms of three types of heterogeneity: (i) Locus Heterogeneity, whereby mutations in different genes cause a similar proteinopathy, as exemplified by mutations in APP, PSEN1 and PSEN2 leading to AD neuropathology; (ii) Allelic Heterogeneity, whereby different mutations in the same gene lead to different proteinopathies or neuropathological severity, as exemplified by different mutations in MAPT and PRNP giving rise to protein species that differ in their biochemistry and affected cell types; and (iii) Phenotypic Heterogeneity, where identical gene mutations lead to different proteinopathies, as exemplified by LRRK2 p.G2019S being associated with variable Lewy body presence and alternative AD neuropathology or FTLD-tau. Of note, the perceived homogeneity in histologic phenotypes may arise from laboratory-specific assessment protocols which can differ in the panel of proteins screened. Finally, the understanding of the complex relationship between genotype and phenotype in dementia families is highly relevant in terms of therapeutic strategies which range from targeting specific genes, to a broader strategy of targeting a downstream, common biochemical problem that leads to the histopathology.

Psychosis and longitudinal outcomes in Huntington disease: the COHORT Study.

OBJECTIVE: Huntington disease (HD) is an autosomal dominant neurodegenerative disease involving motor disturbances, cognitive decline and psychiatric symptoms. Psychotic symptoms occur in a significant proportion of patients. We sought to characterise the clinical outcomes of this group of patients. METHODS: Data were drawn from the Cooperative Huntington Observational Research Trial, a prospective, multi-centre observational study. 1082 patients with HD were recruited. Measures of cognition, function, behavioural disturbance and motor function were completed annually over 5 years. RESULTS: Overall, 190 patients (17.6%) displayed psychotic symptoms. These patients demonstrated worse cognition, function and behavioural disturbances than patients without psychosis over time. Patients with psychosis also demonstrated lower levels of chorea than patients without psychosis, despite adjusting for concurrent antipsychotic and tetrabenazine use. CONCLUSIONS: Psychosis in HD is associated with poorer outcomes in cognition, function and behavioural symptoms. Patients with psychotic symptoms may also have less chorea. Altogether, the findings suggest patients with psychosis have a distinct clinical course.

Associations of Cognitive Function and Education Level With All-Cause Mortality in Adults on Hemodialysis: Findings From the COGNITIVE-HD Study.

RATIONALE & OBJECTIVE: In the general population, cognitive impairment is associated with increased mortality, and higher levels of education are associated with lower risks for cognitive impairment and mortality. These associations are not well studied in patients receiving long-term hemodialysis and were the focus of the current investigation. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adult hemodialysis patients treated in 20 Italian dialysis clinics. EXPOSURES: Patients' cognitive function across 5 domains (memory, attention, executive function, language, and perceptual-motor function), measured using a neuropsychological assessment comprising 10 tests; and patients' self-reported years of education. OUTCOME: All-cause mortality. ANALYTICAL APPROACH: Nested multivariable Cox regression models were used to examine associations of cognition (any domain impaired, number of domains impaired, and global function score from principal components analysis of unadjusted test scores) and education with mortality and whether there were interactions between them. RESULTS: 676 (70.6%) patients participated, with a median age of 70.9 years and including 38.8% women. Cognitive impairment was present in 79.4% (527/664; 95% CI, 76.3%-82.5%). During a median follow-up of 3.3 years (1,874 person-years), 206 deaths occurred. Compared to no cognitive impairment, adjusted HRs for mortality were 1.77 (95% CI, 1.07-2.93) for any impairment, 1.48 (95% CI, 0.82-2.68) for 1 domain impaired, 1.88 (95% CI, 1.01-3.53) for 2 domains, and 2.01 (95% CI, 1.14-3.55) for 3 to 5 domains. The adjusted HR was 0.68 (95% CI, 0.51-0.92) per standard deviation increase in global cognitive function score. Compared with primary or lower education, adjusted HRs were 0.79 (95% CI, 0.53-1.20) for lower secondary and 1.13 (95% CI, 0.80-1.59) for upper secondary or higher. The cognition-by-education interaction was not significant (P=0.7). LIMITATIONS: Potential selection bias from nonparticipation and missing data; no data for cognitive decline; associations with education were not adjusted for other socioeconomic factors. CONCLUSIONS: Cognitive impairment is associated with premature mortality in hemodialysis patients. Education does not appear to be associated with mortality.

Recent Developments in TSPO PET Imaging as A Biomarker of Neuroinflammation in Neurodegenerative Disorders.

Neuroinflammation is an inflammatory response in the brain and spinal cord, which can involve the activation of microglia and astrocytes. It is a common feature of many central nervous system disorders, including a range of neurodegenerative disorders. An overlap between activated microglia, pro-inflammatory cytokines and translocator protein (TSPO) ligand binding was shown in early animal studies of neurodegeneration. These findings have been translated in clinical studies, where increases in TSPO positron emission tomography (PET) signal occur in disease-relevant areas across a broad spectrum of neurodegenerative diseases. While this supports the use of TSPO PET as a biomarker to monitor response in clinical trials of novel neurodegenerative therapeutics, the clinical utility of current TSPO PET radioligands has been hampered by the lack of high affinity binding to a prevalent form of polymorphic TSPO (A147T) compared to wild type TSPO. This review details recent developments in exploration of ligand-sensitivity to A147T TSPO that have yielded ligands with improved clinical utility. In addition to developing a non-discriminating TSPO ligand, the final frontier of TSPO biomarker research requires developing an understanding of the cellular and functional interpretation of the TSPO PET signal. Recent insights resulting from single cell analysis of microglial phenotypes are reviewed.

Prevalence and patterns of cognitive impairment in adult hemodialysis patients: the COGNITIVE-HD study.

Background: Mounting evidence indicates an increased risk of cognitive impairment in adults with end-stage kidney disease on dialysis, but the extent and pattern of deficits across the spectrum of cognitive domains are uncertain. Methods: We conducted a cross-sectional study of 676 adult hemodialysis patients from 20 centers in Italy, aiming to evaluate the prevalence and patterns of cognitive impairment across five domains of learning and memory, complex attention, executive function, language and perceptual-motor function. We assessed cognitive function using a neuropsychological battery of 10 tests and calculated test and domain z-scores using population norms (age or age/education). We defined cognitive impairment as a z-score ≤ -1.5. Results: Participants' median age was 70.9 years (range 21.6-94.1) and 262 (38.8%) were women. Proportions of impairment on each domain were as follows: perceptual-motor function 31.5% (150/476), language 41.2% (273/662), executive function 41.7% (281/674), learning and memory 42.2% (269/638), complex attention 48.8% (329/674). Among 474 participants with data for all domains, only 28.9% (n = 137) were not impaired on any domain, with 25.9% impaired on a single domain (n = 123), 17.3% on two (n = 82), 13.9% on three (n = 66), 9.1% on four (n = 43) and 4.9% (n = 23) on all five. Across patients, patterns of impairment combinations were diverse. Conclusions: In conclusion, cognitive impairment is extremely common in hemodialysis patients, across numerous domains, and patients often experience multiple deficits simultaneously. Clinical care should be tailored to meet the needs of patients with different types of cognitive impairment and future research should focus on identifying risk factors for cognitive decline.

Genetics of dementia.

25% of all people aged 55 years and older have a family history of dementia. For most, the family history is due to genetically complex disease, where many genetic variations of small effect interact to increase risk of dementia. The lifetime risk of dementia for these families is about 20%, compared with 10% in the general population. A small proportion of families have an autosomal dominant family history of early-onset dementia, which is often due to mendelian disease, caused by a mutation in one of the dementia genes. Each family member has a 50% chance of inheriting the mutation, which confers a lifetime dementia risk of over 95%. In this Review, we focus on the evidence for, and the approach to, genetic testing in Alzheimer's disease (APP, PSEN1, and PSEN2 genes), frontotemporal dementia (MAPT, GRN, C9ORF72, and other genes), and other familial dementias. We conclude by discussing the practical aspects of genetic counselling.

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.

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.

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.

Changes in key hypothalamic neuropeptide populations in Huntington disease revealed by neuropathological analyses.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by expansion of a CAG repeat in the HD gene. Degeneration concentrating in the basal ganglia has been thought to account for the characteristic psychiatric symptoms, cognitive decline and motor dysfunction. However, the homeostatic control of emotions and metabolism are disturbed early in HD, and focused studies have identified a loss of orexin (hypocretin) neurons in the lateral hypothalamus in HD patients. There has been limited assessment of other hypothalamic cell populations that may be involved. In this study, we quantified the neuropeptide-expressing hypothalamic neurons known to regulate metabolism and emotion in patients with HD compared to healthy controls using unbiased stereological methods. We confirmed the loss of orexin-expressing neurons in HD and revealed substantial differences in the peptide expression of other neuronal populations in the same patients. Both oxytocin- and vasopressin-expressing neurons were decreased by 45 and 24%, respectively, while the number of cocaine- and amphetamine-regulated transcript (CART)-expressing neurons was increased by 30%. The increased expression of CART in the hypothalamus is consistent with a previous study showing increased CART levels in cerebrospinal fluid from HD patients. There was no difference in the numbers of neuropeptide Y-expressing neurons. These results show significant and specific alterations in the peptide expression of hypothalamic neurons known to regulate metabolism and emotion. They may be important in the development of psychiatric symptoms and metabolic disturbances in HD, and may provide potential targets for therapeutic interventions.

Circular RNAs: The Brain Transcriptome Comes Full Circle.

Circular RNAs (circRNAs) are a class of RNA molecules with a covalently closed loop structure formed by back-splicing of exon-exon junctions. The detection of circRNAs across many eukaryotic species, often with cell-type- and tissue-type-specific expression, has catalyzed a growing interest in understanding circRNA biogenesis and their potential functions. circRNAs are enriched in the brain, and accumulate upon neuronal differentiation and depolarization, suggesting that these RNAs are an integral component of the brain transcriptome, and may play functional roles. Here, we give an overview of the current understanding of circRNA biogenesis and function, discuss how circRNAs contribute to transcriptome complexity in the brain, and discuss recent data on the functional roles of circRNAs in the brain. We also discuss emerging data on the role of circRNAs in brain disorders and address common challenges of circRNA quantification in postmortem human brain.

Making Decisions About Long-Term Institutional Care Placement Among People With Dementia and Their Caregivers: Systematic Review of Qualitative Studies.

BACKGROUND AND OBJECTIVES: People with dementia become increasingly dependent on others for care as cognition declines. Decision making about placement of people with dementia into long-term institutional care can be emotionally complex. The objective of this review is to describe experiences and perspectives of people with dementia and their family caregivers in making decisions about institutional care placement. RESEARCH DESIGN AND METHODS: MEDLINE, Embase, PsycINFO, and CINAHL were searched from inception to August 2018. Thematic synthesis was used to analyze results. RESULTS: We included 42 studies involving 123 people with dementia and 705 family caregivers from 12 countries. We identified five themes: ensuring safety (avoiding injury due to frailty, protecting against dangerous behaviors, preventing aggressive encounters), reaching breaking point (insufferable burden of caregiving, needs exceeding capabilities, intensifying family conflict, loneliness and isolation, straining under additional responsibilities, making extreme personal sacrifices), vulnerability in lacking support (ill-prepared for crisis, unable to access professional expertise, unpredictable prognostic trajectory, uncertainty navigating health care services, pressured by limited placement opportunities, high cost of placement, resenting loss of autonomy), avoiding guilt of abandonment (sharing accountability, mitigating against disagreement and stigma, reluctance to relinquish caregiving, seeking approval), and seeking reassurance and validation (preserving personhood and former identity, empowerment through engagement, assurance of care quality, acceptance from other care residents). DISCUSSION AND IMPLICATIONS: People with dementia and family caregivers feel vulnerable, disempowered, and guilty in decision making about institutionalization. Person-centered communication and support strategies that foster confidence and reassurance are needed to assist people with dementia and caregivers to make decisions about placement into long-term institutional care settings.

Altered serum protein levels in frontotemporal dementia and amyotrophic lateral sclerosis indicate calcium and immunity dysregulation.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that are considered to be on the same disease spectrum because of overlapping genetic, pathological and clinical traits. Changes in serum proteins in FTD and ALS are poorly understood, and currently no definitive biomarkers exist for diagnosing or monitoring disease progression for either disease. Here we applied quantitative discovery proteomics to analyze protein changes in FTD (N = 72) and ALS (N = 28) patient serum compared to controls (N = 22). Twenty three proteins were significantly altered in FTD compared to controls (increased-APOL1, C3, CTSH, EIF5A, MYH2, S100A8, SUSD5, WDR1; decreased-C1S, C7, CILP2, COMP, CRTAC1, EFEMP1, FBLN1, GSN, HSPG2, IGHV1, ITIH2, PROS1, SHBG, UMOD, VASN) and 14 proteins were significantly altered in ALS compared to controls (increased-APOL1, CKM, CTSH, IGHG1, IGKC, MYH2; decreased-C7, COMP, CRTAC1, EFEMP1, FBLN1, GSN, HSPG2, SHBG). There was substantial overlap in the proteins that were altered in FTD and ALS. These results were validated using western blotting. Gene ontology tools were used to assess functional pathways potentially dysregulated in the two diseases, and calcium ion binding and innate immunity pathways were altered in both diseases. When put together, these results suggest significant overlap in pathophysiological peripheral changes in FTD and ALS. This study represents the first proteomics side-by-side comparison of serum changes in FTD and ALS, providing new insights into under-recognized perturbed pathways and an avenue for biomarker development for FTD and ALS.

Growth factors, AGEing, and the diabetes link in Alzheimer's disease.

Diabetes mellitus and Alzheimer's disease (AD) each become increasingly common with age. Diabetes causes many chronic end-organ complications and among them is dementia, which may be due to an underlying vascular cause, as well as being related to AD. The pathogenic mechanisms that lead to diabetes complications include advanced glycation end products (AGEs) and growth factor dysregulation. This review explores the evidence for epidemiological links between diabetes and AD, as well as potential pathogenic mechanisms whereby AGEs, their cellular receptors, and key growth factors may contribute to AD development and progression in diabetes. Directions for future research are also discussed.

Glycogen synthase kinase-3beta and tau genes interact in Alzheimer's disease.

OBJECTIVE: We examined the epistatic effect between haplotypes of glycogen synthase kinase-3beta (GSK3B) gene and microtubule-associated protein Tau (MAPT) gene in Alzheimer's disease (AD). METHODS: A genetic association study of three AD cohorts was made. Linear regression analyses were used to examine effects of MAPT polymorphisms on gene expression and alternative splicing. beta-Catenin levels and signaling were determined using Western blot and luciferase reporter assays in cells transfected with a combination of GSK3B and MAPT complementary DNA. RESULTS: Consistent interaction between GSK3B and MAPT genes in three late-onset AD cohorts was observed, with the GSK3B haplotype (T-T) significantly increasing the risk for AD in individuals with at least one H2 haplotype (odds ratio, 1.68-2.33; p = 0.005-0.036). The GSK3B haplotype was significantly protective in the Chinese cohort (odds ratio, 0.33; p = 0.016), after adjusting for the effect of age and sex. There are significant differences in in vivo transcriptional efficiency between the two MAPT haplotypes (H1 and H2) as determined by measurement of cerebellar transcripts (p < 0.001). Overexpression of either MAPT or GSK3B resulted in decreased beta-catenin levels compared with a control vector (p < 0.001). Conversely, cotransfection of both of these molecules increased beta-catenin signaling. INTERPRETATION: Our genetic and biochemical analyses have identified a novel interaction between Tau and GSK-3beta in late-onset AD causative factors. Our data are consistent with an epistatic model of interaction where discordant levels of GSK3B and MAPT gene expression can lead to altered beta-catenin levels and pathogenicity.

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.