Vascular aging consists of complex and multifaceted processes that may be influenced by genetic polymorphisms of the renin-angiotensin system. A polymorphism in the angiotensin II type 1 receptor gene (AGTR1/rs5186) has been associated with an increased risk for arterial stiffness, hypertension, and ischemic stroke. Despite these identified relationships, the impact of AGTR1 A1166C on white matter integrity and cognition is less clear in a healthy aging population. The present study utilized indices of neuroimaging and neuropsychological assessment to examine the impact of the A1166C polymorphism on subcortical hyperintensities (SH) and cognition in 49 healthy adults between ages 51–85. Using a dominant statistical model (CC + CA (risk) vs. AA), results revealed significantly larger SH volume for individuals with the C1166 variant (p < 0.05, partial eta2 = 0.117) compared with those with the AA genotype. Post hoc analyses indicated that increased SH volume in C allele carriers could not be explained by vascular factors such as pulse pressure or body mass index. In addition, cognitive performance did not differ significantly between groups and was not significantly associated with SH in this cohort. Results suggest that presence of the C1166 variant may serve as a biomarker of risk for suboptimal brain integrity in otherwise healthy older adults prior to changes in cognition.
AGTR1; A1166C; Cerebrovascular aging; Subcortical hyperintensities; Cognition
Traumatic brain injury (TBI) may be a risk factor for criminal behaviour however multiple factors potentially confound the association.
Record linkage and Cox proportional hazards regression analyses were used to examine the association between hospital-recorded TBI (n = 7,694) and subsequent first criminal conviction in a retrospective cohort matched 1:3 with 22,905 unaffected community controls and full-sibling controls (n = 2,397). Aboriginality, substance abuse, social disadvantage, and mental illness were included in analyses as potential confounders
In multivariable models, relative to general population controls, TBI was associated with any conviction (males: Hazard Ratio (HR) = 1·58 (95% CI 1·46 to 1·72); females: HR = 1·52 (95% CI 1·28 to 1·81)); and similar Hazard Ratios were obtained for the sibling analyses in males (HR = 1.68 (95% CI 1.31-2.18)) and females (HR 1.27 (95% CI 0.71-2.29)). TBI was also associated with violent convictions relative to the general population, (males: HR = 1.65 (95% CI 1.42 to 1.92); females HR = 1.73 (95% CI 1.21 to 2.47)), and in analyses with sibling controls in men (HR = 1.89 (95% CI 1.20-3.00)), but not in women (HR 0.73, 95% CI 0.29-1.81)).
The results support a modest causal link between TBI and criminality after comprehensive adjustment for confounding. Reducing the rate of TBI, a major public health imperative, might have benefits in terms of crime reduction.
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.
We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. All participants had 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) and suggestive single-nucleotide polymorphisms.
We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8) that encompassed the HLA locus at 6p21.3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC, for the behavioural FTD subtype. Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation incis.
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 possibly to shed light on the pathomechanisms contributing to FTD.
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.
Patients with coronary heart disease (CHD) who are depressed have an increased risk of further cardiac events and higher mortality.
To use a patient generated instrument (PSYCHLOPS) to define categories of concerns in patients with CHD. To define the psychometric characteristics of patients in each category.
Design and setting
Cross-sectional study set in general practices in south London.
Of 3325 patients on the CHD registers in 15 general practices, 655 completed six baseline psychometric and functional instruments: PSYCHLOPS, HADS-Depression, HADS-Anxiety, Clinical Interview Schedule – Revised, SF12-Mental and SF12-Physical. Content analysis was used to categorise patients based on their main problem, as elicited by PSYCHLOPS. Mean psychometric scores were adjusted for confounding by age, sex, deprivation and ethnicity and calculated for each response category.
Response categories were: physical problems, both non-cardiac (23.2%) and cardiac (6.0%); social problems: relationship/family (18.2%), money (7.5%), work (3.1%); functional (9.8%); psychological (6.9%); miscellaneous (7.3%); ‘no problem’ (18.2%). The highest psychological distress scores were found in ‘physical, cardiac’ and ‘psychological’ categories. The ‘no problem’ category had significantly lower psychological distress and higher functional capacity than other categories.
PSYCHLOPS enabled the identification of subtypes of CHD patients, based on a classification of self-reported problems. A high proportion of CHD patients report social problems. Psychological distress was highest in those reporting cardiac or psychological symptoms. Services should be aligned to the reported needs of patients.
primary care; coronary heart disease; functional capacity measures; mental health outcome measures; patient-generated outcome measures
The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
Hospitalizations for COPD are associated with poor patient prognosis. Length of stay (LOS) of COPD admissions in a large urban area and patient and hospital factors associated with it are described.
Retrospective longitudinal study. All COPD patients registered with London general practitioners and admitted as an emergency with COPD (2006–2010), not having been admitted with COPD in the preceding 12 months were included. Association of patient and hospital characteristics with mean LOS of COPD admissions was assessed. Association between hospital and LOS was determined by negative binomial regression.
The total number of admissions was 38,504, from 22,462 patients. The mean LOS for first admissions fell by 0.8 days (95% confidence interval [CI]: 0.7–1.5) from 8.2 to 7.0 days between 2006 and 2010. Seventy-nine percent of first admissions were ≤10 days, with a mean LOS of 3.7 days (2009–2010). The mean LOS of successive COPD admissions of the same patients was the same or less throughout the study period. The interval between successive admissions fell from a mean of 357 days between the first and second admission to a mean of 19 days after eight admissions. Age accounted for 2.3% of the variance in LOS. Socioeconomic deprivation did not predict LOS. Fewer discharges happened at the weekend (1,893/day) than on weekdays (5,218/day). The mean LOS varied between hospitals, from 4.9 days (95% CI: 3.8–5.9) to 9.5 days (95% CI: 8.6–10.3) when adjusting for clustering, age, sex, and socioeconomic deprivation.
The fall in LOS of the first COPD admission between 2006 and 2010 reflects international trends. The stability of LOS in successive admissions suggests that increasing severity of disease does not affect recovery time from an exacerbation. Variations between hospitals of nearly 5 days in LOS for COPD admissions suggests that significant improvements in patient outcomes and in savings in health care utilization could be made in hospitals with longer LOS.
general practice; hospitalization; LOS
Clinicopathologic evidence suggests the pathology of Alzheimer disease (AD) begins many years prior to cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic (“pre-clinical”) stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study comparing cerebrospinal fluid (CSF), plasma and in vivo amyloid imaging, cross-sectional data obtained at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network (DIAN) demonstrate reduced concentrations of CSF amyloid-β1-42 (Aβ1–42) associated with the presence of β-amyloid plaques, and elevated concentrations of CSF tau, ptau181 and VILIP-1, markers of neurofibrillary tangles and/or neuronal injury/death, in asymptomatic mutation carriers 10-20 years prior to their estimated age at symptom onset (EAO), and prior to detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within-individuals decrease after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.
Quality indicators for primary care focus predominantly on the public health model and organisational measures. Patient experience is an important dimension of quality. Accreditation for GP training practices requires demonstration of a series of attributes including patient-centred care.
The national GP Patient Survey (GPPS) was used to determine the characteristics of general practices scoring highly in responses relating to the professional skills and characteristics of doctors. Specifically, to determine whether active participation in postgraduate GP training was associated with more positive experiences of care.
Design and setting
Retrospective cross-sectional study in general practices in England.
Data were obtained from the national QOF dataset for England, 2011/12 (8164 general practices); the GPPS in 2012 (2.7 million questionnaires in England; response rate 36%); general practice and demographic characteristics. Sensitivity analyses included local data validated by practice inspections. Outcome measures: multilevel regression models adjusted for clustering.
GP training practice status (29% of practices) was a significant predictor of positive GPPS responses to all questions in the ‘doctor care’ (n = 6) and ‘overall satisfaction’ (n = 2) domains but not to any of the ‘nurse care’ or ‘out-of-hours’ domain questions. The findings were supported by the sensitivity analyses. Other positive determinants were: smaller practice and individual GP list sizes, more older patients, lower social deprivation and fewer ethnic minority patients.
Based on GPPS responses, doctors in GP training practices appeared to offer more patient-centred care with patients reporting more positively on attributes of doctors such as ‘listening’ or ‘care and concern’.
medical education; primary health care; quality indicators
Hippocampal atrophy is observed with ageing and age-related neurodegenerative disease. Identification of the genetic correlates of hippocampal volume (HV) and atrophy may assist in elucidating the mechanisms of ageing and age-related neurodegeneration. Using two community cohorts of older Caucasians we estimated the heritability of HV and examined associations of HV with previously identified single nucleotide polymorphisms (SNPs). In addition we undertook genome-association studies (GWAS) examining HV and HV atrophy. Participants were community-dwelling non-demented older adults from the longitudinal Sydney Memory and Ageing Study (Sydney MAS) (N = 498) and the Older Australian Twins Study (OATS) (N = 351) aged 65 and over. HV was measured using T1-weighted magnetic resonance images. Heritability of HV was estimated in OATS. Genome-wide genotyping was imputed using the 1K Genomes reference set. Associations with HV-candidate and Alzheimer’s disease (AD)-related SNPs were investigated. A GWAS examining HV (in both cohorts) and an exploratory GWAS of HV atrophy over two years (in Sydney MAS only) were also undertaken. HV heritability was estimated at 62–65%. The previously identified GWAS HV SNP (rs6581612) and the candidate BDNF SNP (rs6265) were nominally significant (p = 0.047 and p = 0.041 respectively). No AD-related SNPs, including the APOE ε4 polymorphism, were significant. No significant results were observed for either of the GWAS undertaken. Despite our estimate of a high heritability of HV, our results are consistent with a highly polygenic model suggesting that SNPs identified from prior studies, including GWAS meta-analyses, can be difficult to replicate in smaller samples of older adults.
To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD.
We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study.
We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10−16, r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex.
Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research.
The current study sought to examine the relative influence of genetic and environmental factors on corpus callosum (CC) microstructure in a community sample of older adult twins. Analyses were undertaken in 284 healthy older twins (66% female; 79 MZ and 63 DZ pairs) from the Older Australian Twins Study. The average age of the sample was 69.82 (SD = 4.76) years. Brain imaging scans were collected and DTI measures were estimated for the whole CC as well as its five subregions. Parcellation of the CC was performed using Analyze. In addition, white matter lesion (WMLs) burden was estimated. Heritability and genetic correlation analyses were undertaken using the SOLAR software package. Age, sex, scanner, handedness and blood pressure were considered as covariates. Heritability (h2) analysis for the DTI metrics of whole CC, indicated significant h2 for fractional anisotropy (FA) (h2 = 0.56; p = 2.89×10−10), mean diffusivity (MD) (h2 = 0.52; p = 0.30×10−6), radial diffusivity (RD) (h2 = 0.49; p = 0.2×10−6) and axial diffusivity (AD) (h2 = 0.37; p = 8.15×10−5). We also performed bivariate genetic correlation analyses between (i) whole CC DTI measures and (ii) whole CC DTI measures with total brain WML burden. Across the DTI measures for the whole CC, MD and RD shared 84% of the common genetic variance, followed by MD- AD (77%), FA - RD (52%), RD - AD (37%) and FA – MD (11%). For total WMLs, significant genetic correlations indicated that there was 19% shared common genetic variance with whole CC MD, followed by CC RD (17%), CC AD (16%) and CC FA (5%). Our findings suggest that the CC microstructure is under moderate genetic control. There was also evidence of shared genetic factors between the CC DTI measures. In contrast, there was less shared genetic variance between WMLs and the CC DTI metrics, suggesting fewer common genetic variants.
Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic
mutations in three specific genes, in contrast to late-onset Alzheimer
Disease (LOAD), which has a more polygenetic risk profile.
Design, Setting, and Participants
We analyzed functional connectivity in multiple brain resting state
networks (RSNs) in a cross-sectional cohort of ADAD (N=79) and LOAD (N=444)
human participants using resting state functional connectivity MRI
(rs-fcMRI) at multiple international academic sites.
Main Outcomes and Measures
For both types of AD, we quantified and compared functional
connectivity changes in RSNs as a function of dementia severity as measured
by clinical dementia rating (CDR). In ADAD, we qualitatively investigated
functional connectivity changes with respect to estimated years from onset
of symptoms within five RSNs.
Functional connectivity decreases with increasing CDR were similar
for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models
constructed in each type of AD accurately predicted CDR stage in the other,
further demonstrating similarity of functional connectivity loss in each
disease type. Among ADAD participants, functional connectivity in multiple
RSNs appeared qualitatively lower in asymptomatic mutation carriers near
their anticipated age of symptom onset compared to asymptomatic mutation
Conclusions and Relevance
rs-fcMRI changes with progressing AD severity are similar between
ADAD and LOAD. Rs-fcMRI may be a useful endpoint for LOAD and ADAD therapy
trials. ADAD disease process may be an effective model for LOAD disease
Resting-state functional connectivity; autosomal dominant Alzheimer's disease; late-onset Alzheimer's disease; default mode network; apolipoprotein E (APOE)
The most effective treatment for posttraumatic stress disorder (PTSD) is exposure therapy, which aims to facilitate extinction of conditioned fear. Recent evidence suggests that brain-derived neurotrophic factor (BDNF) facilitates extinction learning. This study assessed whether the Met-66 allele of BDNF, which results in lower activity-dependent secretion, predicts poor response to exposure therapy in PTSD.
Fifty-five patients with PTSD underwent an 8-week exposure-based cognitive behavior therapy program and provided mouth swabs or saliva to extract genomic DNA to determine their BDNF Val66Met genotype (30 patients with the Val/Val BDNF allele, 25 patients with the Met-66 allele). We examined whether BDNF genotype predicted reduction in PTSD severity following exposure therapy.
Analyses revealed poorer response to exposure therapy in the PTSD patients with the Met-66 allele of BDNF compared with patients with the Val/Val allele. Pretreatment Clinician Administered PTSD Scale severity and BDNF Val66Met polymorphism predicted response to exposure therapy using hierarchical regression.
This study provides the first evidence that the BDNF Val66Met genotype predicts response to cognitive behavior therapy in PTSD and is in accord with evidence that BDNF facilitates extinction learning.
BDNF; CBT; fear extinction; fMRI; genetics; posttraumatic stress disorder; treatment predictor
Statins are an important intervention for primary and secondary cardiovascular disease (CVD) prevention. We aimed to establish the variation in primary preventive treatment for CVD with statins in the English population.
Cross sectional analyses of 6155 English primary care practices with 40,017,963 patients in 2006/7. Linear regression was used to model prescribing rates of statins for primary CVD prevention as a function of IMD (index of multiple deprivation) quintile, proportion of population from an ethnic minority, and age over 65 years. Defined Daily Doses (DDD) were used to calculate the numbers of patients receiving a statin. Statin prescriptions were allocated to primary and secondary prevention based on the prevalence of CVD and stroke.
We estimated that 10.5% (s.d.3.7%) of the registered population were dispensed a statin for any indication and that 6.3% (s.d. 3.0%) received a statin for primary CVD prevention. The regression model explained 21.2% of the variation in estimates of prescribing for primary prevention. Practices with higher prevalence of hypertension (β co-efficient 0.299 p <0.001) and diabetes (β co-efficient 0.566 p < 0.001) prescribed more statins for primary prevention. Practices with higher levels of ethnicity (β co-efficient-0.026 p <0.001), greater deprivation (β co-efficient −0.152 p < 0.001) older patients (β co-efficient −0.032 p 0.002), larger lists (β co-efficient −0.085, p < 0.001) and were more rural (β co-efficient −0.121, p0.026) prescribed fewer statins. In a small proportion of practices (0.5%) estimated prescribing rates for statins were so low that insufficient prescriptions were issued to meet the predicted secondary prevention requirements of their registered population.
Absolute estimated prescribing rates for primary prevention of CVD were 6.3% of the population. There was evidence of social inequalities in statin prescribing for primary prevention. These findings support the recent introduction of a financial incentive for primary prevention of CVD in England.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6963-14-414) contains supplementary material, which is available to authorized users.
Hydroxymethylglutaryl-CoA reductase inhibitors; Primary health care; Cardiovascular diseases
The epsilon 4 (e4) isoform of apolipoprotein E (ApoE) is a known genetic risk factor for suboptimal brain health. Morphometry studies of brains with Alzheimer’s disease have reported significant alterations in temporal lobe brain structure of e4 carriers, yet it remains unclear if the presence of an e4 allele is associated with alterations in the microstructure of white matter fiber bundles in healthy populations. The present study used quantitative tractography based on diffusion tensor imaging (qtDTI) to examine the influence of the e4 allele on temporal lobe fiber bundle lengths (FBLs) in 64 healthy older adults with at least one e4 allele (carriers, N=23) versus no e4 allele (non-carriers, N=41). Subtests from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were also analyzed to examine memory performance between groups. Analyses revealed shorter FBLs in the left uncinate fasciculus (UF) (p=.038) of e4 carriers compared to non-carriers. By contrast, neither FBLs specific to the temporal lobe nor memory performances differed significantly between groups. Increased age correlated significantly with shorter FBL in the temporal lobe and UF, and with decreased performance on tests of memory. This is the first study to utilize qtDTI to examine relationships between FBL and ApoE genotype. Results suggest that FBL in the UF is influenced by the presence of an ApoE e4 allele (ApoE4) in healthy older adults. Temporal lobe FBLs, however, are more vulnerable to aging than the presence of an e4 allele.
ApoE; ApoE4; Tractography; DTI; White matter; Fiber bundle lengths; Aging
Serious mental illness (SMI) is associated with elevated mortality compared to the general population; the majority of this excess is attributable to co-occurring common physical health conditions. There may be variation within the SMI group in the distribution of physical co/multi-morbidity. This study aims to a) compare the pattern of physical co- and multi-morbidity between patients with and without SMI within a South London primary care population; and, b) to explore socio-demographic and health risk factors associated with excess physical morbidity among the SMI group.
Data were obtained from Lambeth DataNet, a database of electronic patient records derived from general practices in the London borough of Lambeth. The pattern of 12 co-morbid common physical conditions was compared by SMI status. Multivariate ordinal and logistic regression analyses were conducted to assess the strength of association between each condition and SMI status; adjustments were made for potentially confounding socio-demographic characteristics and for potentially mediating health risk factors.
While SMI patients were more frequently recorded with all 12 physical conditions than non-SMI patients, the pattern of co-/multi-morbidity was similar between the two groups. Adjustment for socio-demographic characteristics – in particular age and, to a lesser extent ethnicity, considerably reduced effect sizes and accounted for some of the associations, though several conditions remained strongly associated with SMI status. Evidence for mediation by health risk factors, in particular BMI, was supported.
SMI patients are at an elevated risk of a range of physical health conditions than non-SMI patients but they do not appear to experience a different pattern of co-/multimorbidity among those conditions considered. Socio-demographic differences between the two groups account for some of the excess in morbidity and known health risk factors are likely to mediate the association. Further work to examine a wider range of conditions and health risk factors would help determine the extent of excess mortality attributable to these factors.
Serious mental illness; Mental health; Physical health; Comorbidity; Multimorbidity
Autoimmunity is considered an uncommon but under-recognised cause of cognitive decline.
Serum samples from 3,253 randomly selected subjects enrolled in the Hunter Community Study, aged 55-85 years, were assayed for thyrotropin stimulatory hormone, anti-thyroid peroxidase antibodies (TPO-Ab), anti-nuclear antibodies (ANA) and extractable nuclear antigens (ENA). Cognitive function was assessed using the Audio Recorded Cognitive Screen (ARCS) tool.
TPO-Ab were found in 8.4% and ANA in 27.9% of the study population, of whom 3% had positive ENA findings. No relationship was found between the ARCS score and either TPO-Ab (coefficient = 0.133; 95% CI −0.20, 0.82, p = 0.616), ANA at a low (coefficient = 1.01; 95% CI −2.58, 0.55, p = 0.203) or a high titre (coefficient = −0.65; 95% CI −2.59, 1.28, p = 0.508), or ENA antibodies (coefficient = 5.12; 95% CI −0.53, 10.77; p = 0.076).
Autoantibody findings are common in an aging population and are not associated with cognitive decline.
Dementia; Hashimoto disease; Encephalitis; Autoantibodies; Anti-nuclear antibodies; Nuclear antigens; Autoimmune thyroiditis; Mild cognitive impairment
Familial idiopathic basal ganglia calcification (IBGC) or Fahr’s
disease is a rare neurodegenerative disorder characterized by calcium deposits
in the basal ganglia and other brain regions, which is associated with
neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous
and typically transmitted in an autosomal dominant fashion. We performed a
mutational analysis of SLC20A2, the first gene found to cause
IBGC, to assess its genetic contribution to familial IBGC. We recruited 218
subjects from 29 IBGC-affected families of varied ancestry and collected medical
history, neurological exam, and head CT scans to characterize each
patient’s disease status. We screened our patient cohort for mutations
in SLC20A2. Twelve novel (nonsense, deletions, missense, and
splice site) potentially pathogenic variants, one synonymous variant, and one
previously reported mutation were identified in 13 families. Variants predicted
to be deleterious cosegregated with disease in five families. Three families
showed nonsegregation with clinical disease of such variants, but retrospective
review of clinical and neuroimaging data strongly suggested previous
misclassification. Overall, mutations in SLC20A2 account for as
many as 41 % of our familial IBGC cases. Our screen in a large series
expands the catalog of SLC20A2 mutations identified to date and
demonstrates that mutations in SLC20A2 are a major cause of
familial IBGC. Non-perfect segregation patterns of predicted deleterious
variants highlight the challenges of phenotypic assessment in this condition
with highly variable clinical presentation.
Basal ganglia calcification; Fahr’s; Genetics; Sequencing; Mutations
Health policy in the UK is increasingly focused on the measurement of
outcomes rather than structures and processes of health care.
To develop a measure of the effectiveness of primary care in terms of
population health outcomes.
Design and setting
A cross-sectional study of general practices in England.
Twenty clinical quality of care indicators for which there was evidence of
mortality reduction were identified from the national Quality and Outcomes
Framework (QOF) pay-for-performance scheme. The number of lives saved by
8136 English practices (97.97% of all practices) in 2009/2010 was
estimated, based on their performance on these measures, and a public health
impact measure, the PHI score, was constructed. Multilevel regression models
were used to identify practice and population predictors of PHI scores.
The mean estimated PHI score was 258.9 (standard deviation
[SD] = 73.3) lives saved per 100 000 registered
patients, per annum. This represents 75.7% of the maximum potential
PHI score of 340.9 (SD = 91.8). PHI and QOF scores were weakly
correlated (Pearson r = 0.28). The most powerful predictors of PHI
score were the prevalence of the relevant clinical conditions
(β = 0.77) and the proportion of
patients aged ≥65 years (β = 0.22).
General practices that were less successful at achieving their maximum
potential PHI score were those with a lower prevalence of relevant
conditions (β = 0.29), larger list sizes
(β = −0.16), greater area
deprivation (β = −0.15), and a
larger proportion of patients aged ≥65 years
(β = −0.13).
The PHI score is a potential alternative metric of practice performance,
measuring the estimated mortality reduction in the registered population.
Rewards under the QOF pay-for-performance scheme are not closely aligned to
the public health impact of practices.
health outcomes; population mortality reduction; primary health care
Alpha-2,8-sialyltransferase 2 (ST8SIA2) is an enzyme responsible for the transfer of polysialic acid (PSA) to glycoproteins, principally the neuronal cell adhesion molecule (NCAM1), and is involved in neuronal plasticity. Variants within ST8SIA2 have previously shown association with bipolar disorder, schizophrenia and autism. In addition, altered PSA-NCAM expression in brains of patients with schizophrenia or bipolar disorder indicates a functional dysregulation of glycosylation in mental illness. To explore the role of sequence variation affecting PSA-NCAM formation, we conducted a targeted re-sequencing study of a ∼100 kb region – including the entire ST8SIA2 gene and its region of interaction with NCAM1 – in 48 Caucasian cases with bipolar disorder using the Roche 454 platform. We identified over 400 DNA variants, including 47 putative novel variants not described in dbSNP. Validation of a subset of variants via Sequenom showed high reliability of Roche 454 genotype calls (97% genotype concordance, with 80% of novel variants independently verified). We did not observe major loss-of-function mutations that would affect PSA-NCAM formation, either by ablating ST8SIA2 function or by affecting the ability of NCAM1 to be glycosylated. However, we identified 13 SNPs in the UTRs of ST8SIA2, a synonymous coding SNP in exon 5 (rs2305561, P207P) and many additional non-coding variants that may influence splicing or regulation of ST8SIA2 expression. We calculated nucleotide diversity within ST8SIA2 on specific haplotypes, finding that the diversity on the specific “risk” and “protective” haplotypes was lower than other non-disease-associated haplotypes, suggesting that putative functional variation may have arisen on a spectrum of haplotypes. We have identified common and novel variants (rs11074064, rs722645, 15∶92961050) that exist on a spectrum of haplotypes, yet are plausible candidates for conferring the effect of risk and protective haplotypes via multiple enhancer elements. A Galaxy workflow/pipeline for sequence analysis used herein is available at: https://main.g2.bx.psu.edu/u/a-shaw-neura/p/next-generation-resources.
Clinic-based studies suggest that dementia is diagnosed at older ages in bilinguals compared to monolinguals. The current study sought to test this hypothesis in a large, prospective, community-based study of initially non-demented Hispanic immigrants living in a Spanish-speaking enclave of Northern Manhattan.
Participants included 1,067 participants in the Washington/Hamilton Heights Inwood Columbia Aging Project (WHICAP) who were tested in Spanish and followed at 18–24 month intervals for up to 23 years. Spanish-English bilingualism was estimated via both self-report and an objective measure of English reading level. Multilevel models for change estimated the independent effects of bilingualism on cognitive decline in four domains: episodic memory, language, executive function, and speed. Over the course of the study, 282 participants developed dementia. Cox regression was used to estimate the independent effect of bilingualism on dementia conversion. Covariates included country of origin, gender, education, time spent in the United States, recruitment cohort, and age at enrollment.
Independent of the covariates, bilingualism was associated with better memory and executive function at baseline. However bilingualism was not independently associated with rates of cognitive decline or dementia conversion. Results were similar whether bilingualism was measured via self-report or an objective test of reading level.
This study does not support a protective effect of bilingualism on age-related cognitive decline or the development of dementia. In this sample of Hispanic immigrants, bilingualism is related to higher initial scores on cognitive tests and higher educational attainment and may not represent a unique source of cognitive reserve.
Cognitive aging; episodic memory; executive function; language; statistical modeling
To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network.
Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO).
We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO.
Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.
Traumatic brain injury (TBI) is a common condition that is often complicated by neuropsychiatric sequelae that can have major impacts on function and quality of life. An alteration in the sense of smell is recognized as a relatively common complication of TBI; however in clinical practice, this complication may not be sought or adequately characterized. We conducted a systematic review of studies concerned with olfactory functioning following TBI. Our predetermined criteria led to the identification of 25 studies published in English, which we examined in detail. We have tabulated the data from these studies in eight separate tables, beginning with Table 1, which highlights each study’s key findings, and we provide a summary/synthesis of the findings in the accompanying results and discussion sections. Despite widely differing methodologies, the studies attest to a high frequency of post-TBI olfactory dysfunction and indicate that its presence can serve as a potential marker of additional structural or functional morbidities.
brain injury; olfaction; anosmia; trauma; review
The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
Genetics; MRI; GWAS; Consortium; Meta-analysis; Multi-site
Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association (GWA) study, meta-analysis and follow-up (totaling as many as 18,206 cases and 42,536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7,469 bipolar disorder cases, 1,535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46,160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T], OR = 1.08, P = 6.6 × 10−11). The new variant is located within a 593 kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P = 0.0039 in the public GIANT consortium dataset; P = 0.00047 in 22,651 additional Icelanders).
schizophrenia; bipolar disorder; association; 16p11.2; cross-disorder