Plasma and cerebrospinal fluid concentrations of neurofilament light protein correlate in patients with idiopathic normal pressure hydrocephalus.

BACKGROUND: Neurofilament light chain protein (NFL), a marker of neuronal axonal degeneration, is increased in cerebrospinal fluid (CSF) of patients with idiopathic normal pressure hydrocephalus (iNPH). Assays for analysis of NFL in plasma are now widely available but plasma NFL has not been reported in iNPH patients. Our aim was to examine plasma NFL in iNPH patients and to evaluate the correlation between plasma and CSF levels, and whether NFL levels are associated with clinical symptoms and outcome after shunt surgery. METHODS: Fifty iNPH patients with median age 73 who had their symptoms assessed with the iNPH scale and plasma and CSF NFL sampled pre- and median 9 months post-operatively. CSF plasma was compared with 50 healthy controls (HC) matched for age and gender. Concentrations of NFL were determined in plasma using an in-house Simoa method and in CSF using a commercially available ELISA method. RESULTS: Plasma NFL was elevated in patients with iNPH compared to HC (iNPH: 45 (30-64) pg/mL; HC: 33 (26-50) (median; Q1-Q3), p = 0.029). Plasma and CSF NFL concentrations correlated in iNPH patients both pre- and postoperatively (r = 0.67 and 0.72, p < 0.001). We found only weak correlations between plasma or CSF NFL and clinical symptoms and no associations with outcome. A postoperative NFL increase was seen in CSF but not in plasma. CONCLUSIONS: Plasma NFL is increased in iNPH patients and concentrations correlate with CSF NFL implying that plasma NFL can be used to assess evidence of axonal degeneration in iNPH. This finding opens a window for plasma samples to be used in future studies of other biomarkers in iNPH. NFL is probably not a very useful marker of symptomatology or for prediction of outcome in iNPH.

Epidemiology of suicidal feelings in an ageing Swedish population: from old to very old age in the Gothenburg H70 Birth Cohort Studies.

AIMS: The first aim of this study was to provide prevalence suicidal feelings over time (past week, past month, past year and lifetime) in a population-based sample of old to very old adults without dementia. Does prevalence change with rising age? The second aim was to examine the fluctuation of suicidal feelings over time. How does this coincide with depression status? METHODS: Data were derived from the Gothenburg H70 Birth Cohort Studies (the H70 studies) which are multidisciplinary longitudinal studies on ageing. A representative sample of adults in Gothenburg, Sweden with birth years 1901-1944 were invited to take part in a longitudinal health study on ageing and participated at one or more occasions during 1986-2014. The sample consisted of 6668 observations originating from 3972 participants without dementia between the ages of 70 and 108, including 1604 participants with multiple examination times. Suicidal feelings were examined during a psychiatric interview using the Paykel questions (life not worth living, death wishes, thoughts of taking own life, seriously considered taking life, attempted suicide). RESULTS: Prevalence figures for suicidal feelings of any severity were as follows: past week 4.8%, past month 6.7%, past year 11.2% and lifetime 25.2%. Prevalence rates increased with age in the total group and in women but not in men. Suicidal feelings were common in participants with concurrent major or minor depression, but over a third of the participants who reported suicidal feelings did not fulfil criteria for these diagnoses nor did they present elevated mean depressive symptom scores. The majority of participants consistently reported no experience of suicidal feelings over multiple examination times, but fluctuation was more common in women compared with men. CONCLUSION: Suicidal feelings in late-life are uncommon in individuals without depression indicating that such behaviour is not a widespread, normative phenomenon. However, such feelings may occur outside the context of depression.

Atrial fibrillation increases the risk of dementia amongst older adults even in the absence of stroke.

BACKGROUND: Atrial fibrillation increases risk of stroke, and thus risk of cognitive impairment and dementia. Emerging evidence suggests an association also in the absence of stroke. We aimed to examine the association between atrial fibrillation and incident dementia, with and without exclusion of individuals with stroke, and if sex and genetic factors modify the possible association. METHODS: In 2000-2001, a population-based sample of 70-year-olds (N = 561) underwent comprehensive somatic and neuropsychiatric examinations, as part of the Gothenburg H70 Birth Cohort Studies. Participants were followed up at age 75 and 79. Atrial fibrillation at baseline was identified through ECG, proxy-reports and the National Patient Register (NPR). Stroke at baseline and follow-up was identified through self-reports, proxy-reports and the NPR. Dementia at baseline and follow-up was diagnosed according to the DSM-III-R criteria based on neuropsychiatric examinations, proxy-reports and the NPR. RESULTS: Individuals with atrial fibrillation had an almost threefold increased risk of dementia during 12-year follow-up (HR 2.8; 95% CI 1.3-5.7; P = 0.004), and this risk remained after excluding individuals with stroke at baseline and follow-up. After stratification for sex, the association was only found amongst men (HR 4.6; 95% CI 1.9-11.2; P < 0.001, interaction sex*atrial fibrillation; P = 0.047) and noncarriers of the APOE ε4 allele (HR 4.2; 95% CI 1.8-9.7; P < 0.001, interaction APOE*atrial fibrillation; P = 0.128). Population attributable risk for dementia resulting from atrial fibrillation was 13%. CONCLUSION: The relevance for atrial fibrillation as an indicator of subclinical brain vascular risk needs to be further explored. In addition, patients with atrial fibrillation should be screened for cognitive symptoms.

Depression and neuroticism decrease among women but not among men between 1976 and 2016 in Swedish septuagenarians.

OBJECTIVES: We evaluated birth-cohort differences in depressive symptom burden, prevalence of depression diagnoses, and neuroticism, among Swedish 70-year-olds examined between 1976 and 2016. METHODS: We used a repeated cross-sectional design examining four representative population samples of Swedish 70-year-olds (total n = 2279) with identical methods in 1976-77 (n = 392), 1992-93 (n = 226), 2000-02 (n = 487), and 2014-16 (n = 1166). Depressive symptom burden was rated with the Montgomery Åsberg Depression Rating Scale. Major depression was diagnosed according to DSM-5, and minor depression according to DSM-IV-TR research criteria. Neuroticism was rated with the Eysenck Personality Inventory. RESULTS: For women in 2014-16, MADRS score (4.4 vs. 6.1 vs. 5.8; P < 0.05) and neuroticism (6.6 vs. 7.7 vs. 9.2; P < 0.05) were lower compared with 1992-93 and 1976-77, and the prevalence of any depression was lower compared with 2000-02 and 1992-93 (10.9% vs. 16.9% vs. 18.1%; P < 0.05). For men, we observed no birth-cohort differences in depression, while neuroticism was found to be lower in 2014-16 compared with 1976-77 among men without depression (5.1 vs. 5.9; P < 0.01). The sex difference for MADRS and neuroticism declined between 1976-77 and 2014-16 (cohort*sex P < 0.05). CONCLUSIONS: Depressive burden and neuroticism decreased in 70-year-old women between 1976 and 2016.

Publisher Correction: Preclinical amyloid pathology biomarker positivity: effects on tau pathology and neurodegeneration.

The Article was originally published under a CC BY-NC-ND 4.0 license, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Preclinical amyloid pathology biomarker positivity: effects on tau pathology and neurodegeneration.

Brain autopsy and biomarker studies indicate that the pathology of Alzheimer's disease (AD) is initiated at least 10-20 years before clinical symptoms. This provides a window of opportunity to initiate preventive treatment. However, this emphasizes the necessity for biomarkers that identify individuals at risk for developing AD later in life. In this cross-sectional study, originating from three epidemiologic studies in Sweden (n=1428), the objective was to examine whether amyloid pathology, as determined by low cerebrospinal fluid (CSF) concentration of the 42 amino acid form of ß-amyloid (Aß42), is associated with biomarker evidence of other pathological changes in cognitively healthy elderly. A total of 129 patients were included and CSF levels of Aß42, total tau, tau phosphorylated at threonine 181 (p-tau), neurogranin, VILIP-1, VEGF, FABP3, Aß40, neurofilament light, MBP, orexin A, BDNF and YKL-40 were measured. Among these healthy elderly, 35.6% (N=46) had CSF Aß42 levels below 530 pg ml-1. These individuals displayed significantly higher CSF concentrations of t-tau (P<0.001), p-tau (181) (P<0.001), neurogranin (P=0.009) and FABP3 (P=0.044) compared with amyloid-negative individuals. Our study indicates that there is a subpopulation among healthy older individuals who have amyloid pathology along with signs of ongoing neuronal and synaptic degeneration, as well as tangle pathology. Previous studies have demonstrated that increase in CSF tau and p-tau is a specific sign of AD progression that occurs downstream of the deposition of Aß. On the basis of this, our data suggest that these subjects are at risk for developing AD. We also confirm the association between APOE ɛ4 and amyloid pathology in healthy older individuals.

Heritability and confirmation of genetic association studies for childhood asthma in twins.

BACKGROUND: Although the genetics of asthma has been extensively studied using both quantitative and molecular genetic analysis methods, both approaches lack studies specific to the childhood phenotype and including other allergic diseases. This study aimed to give specific estimates for the heritability of childhood asthma and other allergic diseases, to attempt to replicate findings from genomewide association studies (GWAS) for childhood asthma and to test the same variants against other allergic diseases. METHODS: In a cohort of 25 306 Swedish twins aged 9 or 12 years, data on asthma were available from parental interviews and population-based registers. The interviews also inquired about wheeze, hay fever, eczema, and food allergy. Through structural equation modeling, the heritability of all phenotypes was calculated. A subset of 10 075 twins was genotyped for 16 single nucleotide polymorphisms (SNPs) selected from previous GWAS; these were first tested for association with asthma and significant findings also against the other allergic diseases. RESULTS: The heritability of any childhood asthma was 0.82 (95% CI 0.79-0.85). For the other allergic diseases, the range was approximately 0.60-0.80. Associations for six SNPs with asthma were replicated, including rs2305480 in the GSDMB gene (OR 0.80, 95% CI 0.74-0.86, P = 1.5*10(-8) ; other significant associations all below P = 3.5*10(-4) ). Of these, only rs3771180 in IL1RL1 was associated with any other allergic disease (for hay fever, OR 0.64, 95% CI 0.53-0.77, P = 2.5*10(-6) ). CONCLUSION: Asthma and allergic diseases of childhood are highly heritable, and these high-risk genetic variants associated specifically with childhood asthma, except for one SNP shared with hay fever.

Antisocial behavior and polymorphisms in the oxytocin receptor gene: findings in two independent samples.

The quantitative genetic contribution to antisocial behavior is well established, but few, if any, genetic variants are established as risk factors. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may modulate interpersonal aggression. We here investigated whether single-nucleotide polymorphisms (SNPs) in the OXT receptor gene (OXTR) are associated with the expression of antisocial behavior. A discovery sample, including both sexes, was drawn from the Child and Adolescent Twin Study in Sweden (CATSS; n=2372), and a sample from the Twin Study of Child and Adolescent Development (TCHAD; n=1232) was used for replication. Eight SNPs in OXTR, selected on previous associations with social and antisocial behavior, were genotyped in the participants of CATSS. Significant polymorphisms were subsequently genotyped in TCHAD for replication. Participants completed self-assessment questionnaires-Life History of Aggression (LHA; available only in CATSS), and Self-Reported Delinquency (SRD; available in both samples)-designed to capture antisocial behavior as continuous traits. In the discovery sample, the rs7632287 AA genotype was associated with higher frequency of antisocial behavior in boys, and this was then replicated in the second sample. In particular, overt aggression (directly targeting another individual) was strongly associated with this genotype in boys (P=6.2 × 10(-7) in the discovery sample). Meta-analysis of the results for antisocial behavior from both samples yielded P=2.5 × 10(-5). Furthermore, an association between rs4564970 and LHA (P=0.00013) survived correction in the discovery sample, but there was no association with the SRD in the replication sample. We conclude that the rs7632287 and rs4564970 polymorphisms in OXTR may independently influence antisocial behavior in adolescent boys. Further replication of our results will be crucial to understanding how aberrant social behavior arises, and would support the OXT receptor as one potential target in the treatment of aggressive antisocial behavior.