Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes.

Background: Dementia in Parkinson disease (PD) causes nursing home placement, caregiver distress, higher health care burden, and increased mortality.

Objective: To determine whether the microtubule-associated protein tau (MAPT) H1 haplotype and MAPT subhaplotypes play a role in the risk of PD and Parkinson disease-dementia (PDD) complex.

Design: Case-control genetic analysis.

B cell depletion therapy exacerbates murine primary biliary cirrhosis.

Unlabelled: Primary biliary cirrhosis (PBC) is considered a model autoimmune disease due to the clinical homogeneity of patients and the classic hallmark of antimitochondrial antibodies (AMAs). Indeed, the presence of AMAs represents the most highly directed and specific autoantibody in autoimmune diseases. However, the contribution of B cells to the pathogenesis of PBC is unclear.

IGF-I gene variability is associated with an increased risk for AD.

Insulin-like growth factor I (IGF-I), a neuroprotective factor with a wide spectrum of actions in the adult brain, is involved in the pathogenesis of Alzheimer's disease (AD). Circulating levels of IGF-I change in AD patients and are implicated in the clearance of brain amyloid beta (Aβ) complexes. To investigate this hypothesis, we screened the IGF-I gene for various well known single nucleotide polymorphisms (SNPs) covering % of the gene variability in a population of 2352 individuals.

PICOGEN: five years experience with a genetic counselling program for dementia.

Introduction: We describe the 5 year experience of a genetic counselling program for familial dementias (the PICOGEN program).

Methods: The neurologist selected the candidates for genetic testing in the screening visit based on family history and phenotype (Alzheimer disease-AD, frontotemporal lobar degeneration-FTLD, or prion disease). Asymptomatic subjects who decided to know their genetic status were evaluated within a structured protocol by the psychiatrist and psychologist prior to entering the program and followed up afterwards.

Cardiac sympathetic impairment parallels nigrostriatal degeneration in Probable Dementia with Lewy Bodies.

Aim: Dementia with Lewy Bodies (DLB) must be distinguished from other types of dementia because of important differences in patient management and outcome. Both reduction in cardiac 123I-metaiodobenzilguanidine (MIBG) uptake and decreased 123I-FP-CIT binding in basal ganglia have been described in DLB. The aim of this study was to assess the relationship between cardiac sympathetic activity and nigrostriatal degeneration in patients with probable DLB.

Tau phosphorylation and aggregation as a therapeutic target in tauopathies.

Tauopathies are neurodegenerative diseases characterized by insoluble hyperphosphorylated deposits of the microtubule-associated protein tau in the central nervous system. In these disorders, tau is believed to cause neurodegeneration and neuronal loss due to the loss of function of the normal protein, and/or the gain of toxic properties by generating multimeric species. The obstacles found in amyloid-based therapies in Alzheimer's disease, the most common tauopathy, have stimulated the search for alternative targets, including tau.

PBC screen: an IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis.

A dual isotype (IgG, IgA) enzyme-linked immunosorbent assay (ELISA) designed to provide enhanced detection of primary biliary cirrhosis (PBC)-specific autoantibodies against both major mitochondrial and nuclear antigens has been developed and recently become commercially available. The assay (PBC Screen) simultaneously detects IgG and IgA autoantibodies to the immunodominant portions of the 3 major mitochondrial (MIT3) and nuclear (gp210, and sp100) antigens. The aim of this study was to compare the performance of the PBC Screen to the combined performance obtained with individual IgG ELISAs to MIT3, gp210, and sp100 on a large group of selected patients from multiple centers.

The effect of MAPT H1 and APOE ε4 on transition from mild cognitive impairment to dementia.

Microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) are involved in the pathogenic mechanisms of Alzheimer's disease (AD). We prospectively followed three longitudinal independent samples (total n=319) with amnestic mild cognitive impairment (MCI) and analyzed whether MAPT H1/H2 haplotypes and APOE ε4 polymorphisms accelerated the rate of progression from MCI to dementia. At the end of the study, 172 subjects remained cognitively stable, whereas 147 progressed to dementia.

Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune chronic cholestatic liver disease with a strong genetic susceptibility due to the high concordance in monozygotic (MZ) twins and a striking female predominance. Women with PBC manifest an enhanced X monosomy rate in peripheral lymphocytes and we thus hypothesized an X chromosome epigenetic component to explain PBC female prevalence. While most genes on the female inactive X chromosome are silenced by promoter methylation following X chromosome inactivation (XCI), approximately 10% of X- linked genes exhibit variable escape from XCI in healthy females.

Primary biliary cirrhosis and autoimmune hepatitis: apotopes and epitopes.

Autoimmune liver diseases (ALDs) represent a wide spectrum of chronic inflammatory diseases that are characterized by an immune-mediated attack against either hepatocytes (in the case of autoimmune hepatitis types 1 and 2, AIH-1, 2) or cholangiocytes (in primary biliary cirrhosis, PBC). PBC is considered a model autoimmune disease due to the homogeneity of patients, the high specificity of antimitochondrial antibodies (AMAs), and the specificity of biliary epithelial cell (BEC) destruction. It ensues from a multi-lineage loss of tolerance to the E2 component of the pyruvate dehydrogenase complex (PDC-E2).

beta-Amyloid disrupts activity-dependent gene transcription required for memory through the CREB coactivator CRTC1.

Activity-dependent gene expression mediating changes of synaptic efficacy is important for memory storage, but the mechanisms underlying gene transcriptional changes in age-related memory disorders are poorly understood. In this study, we report that gene transcription mediated by the cAMP-response element binding protein (CREB)-regulated transcription coactivator CRTC1 is impaired in neurons and brain from an Alzheimer's disease (AD) transgenic mouse expressing the human beta-amyloid precursor protein (APP(Sw,Ind)). Suppression of CRTC1-dependent gene transcription by beta-amyloid (Abeta) in response to cAMP and Ca(2+) signals is mediated by reduced calcium influx and disruption of PP2B/calcineurin-dependent CRTC1 dephosphorylation at Ser151.

Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis.

Unlabelled: Our understanding of primary biliary cirrhosis (PBC) has been significantly enhanced by the rigorous dissection of the multilineage T and B cell response against the immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2). PDC-E2 is a ubiquitous protein present in mitochondria of nucleated cells. However, the damage of PBC is confined to small biliary epithelial cells (BECs).

Genetic associations in Italian primary sclerosing cholangitis: heterogeneity across Europe defines a critical role for HLA-C.

Background & Aims: The HLA complex on chromosome 6p21 is firmly established as a risk locus for primary sclerosing cholangitis (PSC). We aimed to exploit genetic differences between Northern Europe and Italy in an attempt to define a causative locus in this genetic region.

Methods: Seventy-eight North-Italian PSC patients and 79 controls were included.

Triflusal reduces dense-core plaque load, associated axonal alterations and inflammatory changes, and rescues cognition in a transgenic mouse model of Alzheimer's disease.

Inflammation has been associated with the two classic lesions in the Alzheimer's (AD) brain, amyloid deposits and neurofibrillary tangles. Recent data suggest that Triflusal, a compound with potent anti-inflammatory effects in the central nervous system in vivo, might delay the conversion from amnestic mild cognitive impairment to a fully established clinical picture of dementia. In the present study, we investigated the effect of Triflusal on brain Abeta accumulation, neuroinflammation, axonal curvature and cognition in an AD transgenic mouse model (Tg2576).

A qualitative assessment of the concept of dependence in Alzheimer's disease.

Background: The Dependence Scale (DS) was designed to assess levels of patient need for care due to deficits typical of Alzheimer's disease (AD). This study examined content validity of the DS based on input from patients, caregivers, and clinicians.

Methods: Qualitative interviews with experts, patients, and caregivers were used to collect information on the concept of dependence and to assess content validity.

A megalin polymorphism associated with promoter activity and Alzheimer's disease risk.

Elevated cerebral levels of amyloid beta-protein (Abeta) occur in Alzheimer's disease (AD), yet only a few patients show evidence of increased Abeta production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of Abeta. Megalin, which plays an important role in mediating Abeta clearance, is an attractive candidate gene for genetic association with AD.

gamma-Secretase as a therapeutic target in Alzheimer's disease.

gamma-Secretase is an intramembranous multi-protein complex that cleaves many type-I proteins with critical roles in neuronal function. In Alzheimer's disease (AD) interest in gamma-secretase comes, in part, from the fact that this complex is responsible for the last cleavage step of the amyloid precursor protein (APP) that generates the amyloid-beta peptide (Abeta). Abeta represents the primary component of the amyloid plaque, one of the main pathological hallmarks of AD.

Clinical, neuropathologic, and biochemical profile of the amyloid precursor protein I716F mutation.

We report the clinical, pathologic, and biochemical characteristics of the recently described amyloid precursor protein (APP) I716F mutation. We present the clinical findings of individuals carrying the APP I716F mutation and the neuropathologic examination of the proband. The mutation was found in a patient with Alzheimer disease with onset at the age of 31 years and death at age 36 years and who had a positive family history of early-onset Alzheimer disease.

Definition of human autoimmunity--autoantibodies versus autoimmune disease.

The critical function of the immune system is to discriminate self from non-self. Tolerance against self-antigens is a highly regulated process and, in order to maintain it, the immune system must be able to distinguish self-reactive lymphocytes as they develop. The presence of autoantibodies is the consequence of breakdown of tolerance and, although they are an important serological feature of autoimmune diseases, their presence is not exclusive of these conditions.

Treatment with PEG-interferon and ribavirin for chronic hepatitis C increases neutrophil and monocyte chemotaxis.

The incidence of infections increases during treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV) for chronic hepatitis C (CHC). Despite a reduction in neutrophil count, there is no clear relationship between infection occurrence and neutropenia. In the present study we investigated whether HCV treatment alters leukocyte function.

A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo.

Amyloid deposits, neurofibrillary tangles, and neuronal cell death in selectively vulnerable brain regions are the chief hallmarks in Alzheimer's (AD) brains. Glycogen synthase kinase-3 (GSK-3) is one of the key kinases required for AD-type abnormal hyperphosphorylation of tau, which is believed to be a critical event in neurofibrillary tangle formation. GSK-3 has also been recently implicated in amyloid precursor protein (APP) processing/Abeta production, apoptotic cell death, and learning and memory.

Mild cholesterol depletion reduces amyloid-beta production by impairing APP trafficking to the cell surface.

It has been suggested that cellular cholesterol levels can modulate the metabolism of the amyloid precursor protein (APP) but the underlying mechanism remains controversial. In the current study, we investigate in detail the relationship between cholesterol reduction, APP processing and gamma-secretase function in cell culture studies. We found that mild membrane cholesterol reduction led to a decrease in Abeta(40) and Abeta(42) in different cell types.

Primary biliary cirrhosis is associated with altered hepatic microRNA expression.

MicroRNAs (miRNAs) are small RNA molecules that negatively regulate protein coding gene expression and are thought to play a critical role in many biological processes. Aberrant levels of miRNAs have been associated with numerous diseases and cancers, and as such, miRNAs have gain much interests as diagnostic biomarkers, and as therapeutic targets. However, their role in autoimmunity is largely unknown.

Innate immunity and primary biliary cirrhosis.

There has been a rapid growth in our understanding of the molecular bases of primary biliary cirrhosis (PBC). These efforts were initiated when the immunodominant mitochondrial autoantigen was cloned and sequenced. Using the recombinant cloned antigen as a tool, research has focused on the effector mechanisms of disease and the uniqueness of the primary target tissue, the intrahepatic bile ducts.