Age-related hearingimpairment and frailty in Alzheimer’s disease: interconnected associations and mechanisms

Among potentially modifiable age-related conditions linked to dementia, Alzheimer’s disease (AD),and late-life cognitive disorders, age-related hearing impairment (ARHI) or resbycusis is themost widely diffused sensory disorder and one of the principal causes of chronic disability inolder adults (Gates and Mills, 2005). The impairments of peripheral (sensory or strial) and central(predominantly neural) auditory pathways, diagnosed with different procedures, are often variouslyimbricated in determining ARHI, with mixed clinical findings (Gates and Mills, 2005). A growingbody of epidemiological evidence linking ARHI with late-life cognitive disorders (Panza et al.,2015a) suggested the potential for correcting hearing loss so that elders can function better alsofrom a cognitive point of view with appropriate treatment.ARHI is also a substantial marker for frailty in older age, another age-related clinical conditionfor identifying older persons at elevated risk for numerous adverse health outcomes such asfalls, institutionalization, hospitalization, disability, and death (Rodríguez-Mañas, 2013). Frailtyis as a multidimensional syndrome characterized by a nonspecific state of vulnerability, reducedmultisystem physiological reserve, and decreased resistance to stressors (Rodríguez-Mañas, 2013).Although there is no consensus regarding the operational definition of frailty, in general, twoare the most frequently used approaches: the first is the physical or “phenotypic” model offrailty, while the second is based on deficit accumulation, measured with the so called frailtyindexes, and defined as an accumulation of health-related deficits and disorders (Rodríguez-Mañas,2013). However, also psychological, cognitive and social factors are part of this multidimensionalsyndrome, with great influence on its definition and treatment. Cognition has already beensuggested as a possible component of frailty with increased risk of adverse outcomes. Therefore, theprevention of cognitive-related adverse outcomes including delirium (Eeles et al., 2012) and late-life cognitive disorders (Robertson et al., 2013; Panza et al., 2015b) may be possible also throughfrailty prevention

Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia

Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disease, still a significant number of families and sporadic cases remains genetically unsolved. We performed whole exome sequencing in 100 patients with a late-onset and heterogeneous FTD-like clinical phenotype from Apulia and screened mendelian dementia and neuronal ceroid lipofuscinosis genes. We identified a nonsense mutation in SORL1 VPS domain (p.R744X), in 2 siblings displaying AD with severe language problems and primary progressive aphasia and a near splice-site mutation in CLCN6 (p.S116P) segregating with an heterogeneous phenotype, ranging from behavioural FTD to FTD with memory onset and to the logopenic variant of primary progressive aphasia in one family. Moreover 2 sporadic cases with behavioural FTD carried heterozygous mutations in the CSF1R Tyrosin kinase flanking regions (p.E573K and p.R549H). By contrast, only a minority of patients carried pathogenic C9orf72 repeat expansions (1%) and likely moderately pathogenic variants in GRN (p.C105Y, p.C389fs and p.C139R) (3%). In concert with recent studies, our findings support a common pathogenic mechanisms between FTD and neuronal ceroid lipofuscinosis and suggests that neuronal ceroid lipofuscinosis genes should be investigated also in dementia patients with predominant frontal symptoms and language impairments

The prevalence of peripheral and central hearing impairment and its relation to cognition in older adults.

Age-related hearing loss (ARHL) and dementia are two highly prevalent conditions in the adult population. Recent studies have suggested that hearing loss is independently associated with poorer cognitive functioning. The aim of this study was to evaluate the prevalence of ARHL and cognitive impairment in a large sample of subjects older than 65 years and to correlate hearing function with cognitive function. A total of 488 subjects older than 65 years (mean age 72.8 years) participating in the Great Age Study underwent a complete audiological, neurological and neuropsychological evaluation as part of a multidisciplinary assessment. The prevalence of a hearing loss greater than 25 dB HL was 64.1%, of Central Auditory Processing Disorder (CAPD) was 14.3 and 25.3% of the subjects reported a hearing handicap as reported on the Hearing Handicap Inventory for the Elderly Screening Version questionnaire. Multiple logistic regression analysis corrected for gender, age and education duration showed that mild cognitive impairment (MCI) was significantly associated with hearing impairment (CAPD and hearing threshold; odds ratio 1.6, p = 0.05) and that Alzheimer's disease (AD) was significantly associated with CAPD (odds ratio 4.2, p = 0.05). Given that up to 80% of patients affected by MCI convert to AD, adding auditory tests to a screening cognitive battery might have value in the early diagnosis of cognitive decline

The Role of Age on Beta-Amyloid1–42 Plasma Levels in Healthy Subjects

Beta-amyloid (Ab) plaques have been observed in the brain of healthy elderlies with frequencies strongly influenced by age. The aim of the study is to evaluate the role of age and other biochemical and hematological parameters on Ab1–42 plasma levels in cognitively and neurologically normal individuals. Two-hundred and seventy-five normal subjects stratified by age groups (<35 years, 35–65 years, and >65 years) were included in the study. Ab1–42 plasma levels significantly correlated with age (rs = 0.27; p < 0.0001) in the whole sample, inversely correlated with age in the first age group (rs = 0.25, p = 0.01), positively correlated in the second group (rs = 0.22, p = 0.03), while there was no significant correlation in the older group (rs = 0.02, p = 0.86). Both age (b- estimate = 0.08; p < 0.001) and cholesterol (b-estimate = 0.03; p = 0.009) were significantly associated with Ab1–42 plasma level in multivariable analysis. However, only the association with age survived post hoc adjustment for multiple comparisons. The different effects of age on the Ab level across age groups should be explored in further studies to better understand the age-dependent variability. This could better define the value of plasma Ab as a biomarker of the Alzheimer neuropathology

Valorización económica de la implementación de una estrategia sanitaria de control del virus de la diarrea viral bovina en un establecimiento de cría

El virus de la Diarrea Viral Bovina (vDVB) causa importantes pérdidas económicas en la ganadería bovina. Una situación relevante es la existencia de bovinos persistentemente infectados (PI) producto de la exposición congénita al virus; estos animales son el principal reservorio y fuente de diseminación del virus por lo que la detección y eliminación de estos animales PI es la base de un programa racional para el control del vDVB. Como en otras enfermedades, la DVB tiene la desventaja de que las pérdidas no son fácilmente cuantificables, por lo que existe falta de conocimiento de su real implicancia en la producción. El objetivo del presente trabajo fue valorizar económicamente la implementación de una Estrategia Sanitaria de Control del vDVB en un rodeo de cría del sudeste bonaerense.Trabajo premiado con el Premio Mención Biogénesis-Bagó, versión 2015.Academia Nacional de Agronomía y Veterinari

Valorización económica de la implementación de una estrategia sanitaria de control del virus de la diarrea viral bovina en un establecimiento de cría

El virus de la Diarrea Viral Bovina (vDVB) causa importantes pérdidas económicas en la ganadería bovina. Una situación relevante es la existencia de bovinos persistentemente infectados (PI) producto de la exposición congénita al virus; estos animales son el principal reservorio y fuente de diseminación del virus por lo que la detección y eliminación de estos animales PI es la base de un programa racional para el control del vDVB. Como en otras enfermedades, la DVB tiene la desventaja de que las pérdidas no son fácilmente cuantificables, por lo que existe falta de conocimiento de su real implicancia en la producción. El objetivo del presente trabajo fue valorizar económicamente la implementación de una Estrategia Sanitaria de Control del vDVB en un rodeo de cría del sudeste bonaerense.Trabajo premiado con el Premio Mención Biogénesis-Bagó, versión 2015.Academia Nacional de Agronomía y Veterinari

Frontotemporal dementia and its subtypes: a genome-wide association study

SummaryBackground Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with {FTD} and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with {FTD} and 4308 controls), we did separate association analyses for each {FTD} subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and {FTD} overlapping with motor neuron disease FTD-MND), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, \{HLA\} locus (immune system), for rs9268877 (p=1·05 × 10−8; odds ratio=1·204 95% \{CI\} 1·11–1·30), rs9268856 (p=5·51 × 10−9; 0·809 0·76–0·86) and rs1980493 (p value=1·57 × 10−8, 0·775 0·69–0·86) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural \{FTD\} subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10−7; 0·814 0·71–0·92). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe