Abstract
Objectives
To examine the effect of perceived loneliness on the development of dementia (all-cause), Alzheimer´s disease (AD), and vascular dementia (VaD).
Method
The study comprised 1,905 ...nondemented participants at baseline, drawn from the longitudinal Betula study in Sweden, with a follow-up time of up to 20 years (mean 11.1 years). Loneliness was measured with a single question: “Do you often feel lonely?”.
Results
During the follow-up, 428 developed dementia; 221 had AD, 157 had VaD, and 50 had dementia of other subtypes. The entire dementia group is denoted “all-cause dementia.” Cox regression models, adjusted for age, gender, and a baseline report of perceived loneliness, showed increased risk of all-cause dementia (hazard ratio HR = 1.46, 95% confidence interval CI 1.14–1.89), and AD (HR = 1.69, 95% CI 1.20–2.37), but not VaD (HR = 1.34, 95% CI 0.87–2.08). After adjusting for a range of potential confounders, and excluding participants with dementia onset within the first 5 years of baseline (to consider the possibility of reverse causality), the increased risk for the development of all-cause dementia and AD still remained significant (HR = 1.51, 95% CI 1.01–2.25 for all-cause dementia; HR = 2.50, 95% CI 1.44–4.36 for AD).
Discussion
The results suggest that perceived loneliness is an important risk factor for all-cause dementia and especially for AD, but not for VaD. These results underscore the importance of paying attention to subjective reports of loneliness among the elderly adults and identifying potential intervention strategies that can reduce loneliness.
Objectives
To determine whether dementia could explain the association between poor olfactory performance and mortality risk within a decade‐long follow‐up period.
Design
Prospective cohort study.
...Setting
Betula Study, Umeå, Sweden.
Participants
A population‐based sample of adult participants without dementia at baseline aged 40 to 90 (N = 1,774).
Measurements
Olfactory performance using the Scandinavian Odor‐Identification Test (SOIT) and self‐reported olfactory function; several social, cognitive, and medical risk factors at baseline; and incident dementia during the following decade.
Results
Within the 10‐year follow‐up, 411 of 1,774 (23.2%) participants had died. In a Cox model, the association between higher SOIT score and lower mortality was significant (hazard ratio (HR) = 0.74 per point interval, 95% confidence interval (CI) = 0.71–0.77, P < .001). The effect was attenuated, but remained significant, after controlling for age, sex, education, and health‐related and cognitive variables (HR = 0.92, 95% CI = 0.87–0.97, P = .001). The association between SOIT score and mortality was retained after controlling for dementia conversion before death (HR = 0.92, 95% CI = 0.87–0.97, P = .001). Similar results were obtained for self‐reported olfactory dysfunction.
Conclusion
Poor odor identification and poor self‐reported olfactory function are associated with greater likelihood of future mortality. Dementia does not attenuate the association between olfactory loss and mortality, suggesting that olfactory loss might mark deteriorating health, irrespective of dementia.
Most people's cognitive abilities decline with age, with significant and partly genetically driven, individual differences in rate of change. Although APOE ɛ4 and genetic scores for late-onset ...Alzheimer's disease (LOAD) have been related to cognitive decline during preclinical stages of dementia, there is limited knowledge concerning genetic factors implied in normal cognitive aging. In the present study, we examined three potential genetic predictors of age-related cognitive decline as follows: (1) the APOE ɛ4 allele, (2) a polygenic score for general cognitive ability (PGS-cog), and (3) a polygenic risk score for late-onset AD (PRS-LOAD). We examined up to six time points of cognitive measurements in the longitudinal population-based Betula study, covering a 25-year follow-up period. Only participants that remained alive and non-demented until the most recent dementia screening (1-3 years after the last test occasion) were included (n = 1087). Individual differences in rate of cognitive change (composite score) were predicted by the PRS-LOAD and APOE ɛ4, but not by PGS-cog. To control for the possibility that the results reflected a preclinical state of Alzheimer's disease in some participants, we re-ran the analyses excluding cognitive data from the last test occasion to model cognitive change up-until a minimum of 6 years before potential onset of clinical Alzheimers. Strikingly, the association of PRS-LOAD, but not APOE ɛ4, with cognitive change remained. The results indicate that PRS-LOAD predicts individual difference in rate of cognitive decline in normal aging, but it remains to be determined to what extent this reflects preclinical Alzheimer's disease brain pathophysiology and subsequent risk to develop the disease.
Introduction
We investigated neurofilament light (NFL) accumulation in normal aging as well as in preclinical and clinical Alzheimer's disease (AD) and assessed individual differences in NFL load in ...relation to cognition and brain white‐matter integrity.
Methods
We analyzed longitudinal data covering 30 years (1988–2017). Cognitive testing was done up to six times. Plasma NFL was quantified for controls and 142 cases who developed AD over time, and longitudinal changes in NFL were quantified for 100 individuals with three brain‐imaging sessions.
Results
Longitudinal analyses revealed age‐related NFL increases with marked variability. AD cases had elevated NFL levels, while no significant group differences were seen in the preclinical phase. Variability in NFL levels showed non‐significant correlations with cognition but was associated with brain white matter.
Discussion
Our findings suggest that elevated blood NFL, likely reflecting brain white‐matter alterations, characterizes clinical AD, while NFL levels do not predict age‐related cognitive impairment or impending AD.
Abstract
Polygenic risk for schizophrenia has been associated with lower cognitive ability and age-related cognitive change in healthy individuals. Despite well-established neuropsychological sex ...differences in schizophrenia patients, genetic studies on sex differences in schizophrenia in relation to cognitive phenotypes are scarce. Here, we investigated whether the effect of a polygenic risk score (PRS) for schizophrenia on childhood, midlife, and late-life cognitive function in healthy individuals is modified by sex, and if PRS is linked to accelerated cognitive decline. Using a longitudinal data set from healthy individuals aged 25–100 years (
N
= 1459) spanning a 25-year period, we found that PRS was associated with lower cognitive ability (episodic memory, semantic memory, visuospatial ability), but not with accelerated cognitive decline. A significant interaction effect between sex and PRS was seen on cognitive task performance, and sex-stratified analyses showed that the effect of PRS was male-specific. In a sub-sample, we observed a male-specific effect of the PRS on school performance at age 12 (
N
= 496). Our findings of sex-specific effects of schizophrenia genetics on cognitive functioning across the lifespan indicate that the effects of underlying disease genetics on cognitive functioning is dependent on biological processes that differ between the sexes.
Abstract Introduction The objective was to examine whether subjective memory impairment (SMI) predicts all-cause dementia or Alzheimer's disease (AD) in a population-based study with long-term ...follow-up (median = 10 years). Methods A total of 2043 initially dementia-free participants (≥ 60 years) made three memory ratings (“compared with others”, “compared with five years ago”, and “complaints from family/friends”) at baseline. During follow-up, 372 participants developed dementia (208 with AD). Results Cox regression revealed that subjective memory impairment ratings predicted all-cause dementia in models adjusting for age and sex (hazard ratio or HR from 2.04 to 3.94), with even higher values for AD (HR from 2.29 to 5.74). The result persisted in models including other covariates, including baseline episodic memory performance, and in analyses restricted to participants with long time to dementia diagnosis (≥ 5 years). Discussion The findings underscore the usefulness of subjective memory assessment in combination with other factors in identifying individuals at risk for developing dementia.
Transcription factor programming of pluripotent stem cells (PSCs) has emerged as an approach to generate human neurons for disease modeling. However, programming schemes produce a variety of ...cell types, and those neurons that are made often retain an immature phenotype, which limits their utility in modeling neuronal processes, including synaptic transmission. We report that combining NGN2 programming with SMAD and WNT inhibition generates human patterned induced neurons (hpiNs). Single-cell analyses showed that hpiN cultures contained cells along a developmental continuum, ranging from poorly differentiated neuronal progenitors to well-differentiated, excitatory glutamatergic neurons. The most differentiated neurons could be identified using a CAMK2A::GFP reporter gene and exhibited greater functionality, including NMDAR-mediated synaptic transmission. We conclude that utilizing single-cell and reporter gene approaches for selecting successfully programmed cells for study will greatly enhance the utility of hpiNs and other programmed neuronal populations in the modeling of nervous system disorders.
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•Coupling NGN2 expression and SMAD/WNT inhibition yields human patterned induced neurons (hpiNs)•Single-cell analysis indicates excitatory, neuronal identity, with variable maturity•A CAMK2A::GFP reporter gene isolates more differentiated neurons from progenitors•CAMK2A+ hpiNs display AMPAR- and NMDAR-mediated synaptic transmission
Nehme et al. combine two strong neuralizing factors (transcription factor programming and small molecule patterning) to generate human excitatory neurons from stem cells. They further undertake single-cell and reporter gene approaches to select highly differentiated neurons with increased functionality, augmenting their utility in the modeling of nervous system disorders.
We examined whether conversion to dementia can be predicted by self-reported olfactory impairment and/or by an inability to identify odors. Common forms of dementia involve an impaired sense of ...smell, and poor olfactory performance predicts cognitive decline among the elderly. We followed a sample of 1529 participants, who were within a normal range of overall cognitive function at baseline, over a 10-year period during which 159 were classified as having a dementia disorder. Dementia conversion was predicted from demographic variables, Mini-Mental State Examination score, and olfactory assessments. Self-reported olfactory impairment emerged as an independent predictor of dementia. After adjusting for effects of other predictors, individuals who rated their olfactory sensitivity as "worse than normal" were more likely to convert to dementia than those who reported normal olfactory sensitivity (odds ratio OR = 2.17; 95% confidence interval CI 1.40, 3.37). Additionally, low scores on an odor identification test also predicted conversion to dementia (OR per 1 point increase = 0.89; 95% CI 0.81, 0.98), but these two effects were additive. We suggest that assessing subjective olfactory complaints might supplement other assessments when evaluating the risk of conversion to dementia. Future studies should investigate which combination of olfactory assessments is most useful in predicting dementia conversion.
Depression in unipolar and bipolar disorders is associated with hypothalamic-pituitary-adrenal-axis (HPA-axis) hyperactivity. Also, unipolar disorder has recently been shown to exhibit HPA-axis ...hypoactivity. We studied for the first time how HPA-axis hypo- and hyperactivity relate to depression and disease burden in bipolar disorder. We were interested in studying hypocortisolism; characterized by increased HPA-axis negative feedback sensitivity and lower basal cortisol levels together with the opposite HPA-axis regulatory pattern of hypercortisolism.
This cross-sectional study includes 145 type 1 and 2 bipolar outpatients and 145 matched controls. A dexamethasone-suppression-test (DST) measures the negative feedback sensitivity and a weight-adjusted very-low-dose DST was employed, which is sensitive in identifying hypocortisolism and hypercortisolism. The 25th and 75th percentiles of control post-DST values were used as cut-offs identifying patients exhibiting relative hypo-, and hypercortisolism. Self-report questionnaires were employed: Beck-Depression-Inventory (BDI), Montgomery-Åsberg-Depression-Rating-Scale (MADRS-S), World-Health-Organization-Quality-of-Life-Assessment-100 and Global-Assessment-of-Functioning.
Patients exhibiting relative hypocortisolism expectedly exhibited lowered basal cortisol levels (p = 0.046). Patients exhibiting relative hypercortisolism expectedly exhibited elevated basal levels (p<0.001). Patients exhibiting relative hypocortisolism showed 1.9-2.0 (BDI, p = 0.017, MADRS-S, p = 0.37) and 6.0 (p<0.001) times increased frequencies of depression and low overall life quality compared with patients exhibiting mid post-DST values (eucortisolism). Adjusted Odds Ratios (OR:s) for depression ranged from 3.8-4.1 (BDI, p = 0.006, MADRS-S, p = 0.011) and was 23.4 (p<0.001) for life quality. Patients exhibiting relative hypercortisolism showed 1.9-2.4 (BDI, p = 0.017, MADRS-S, p = 0.003) and 4.7 (p<0.001) times higher frequencies of depression and low overall life quality compared with patients exhibiting eucortisolism. Adjusted OR:s for depression ranged from 2.2-2.7 (BDI, p = 0.068, MADRS-S, p = 0.045) and was 6.3 (p = 0.008) for life quality.
The cross-sectional design and lack of pre-established reference values of the DST employed.
Relative hypocortisolism and relative hypercortisolism were associated with depression and lower life quality, providing novel insights into the detrimental role of stress in bipolar disorder.