Psychological stress, cognitive decline and the development of dementia in amnestic mild cognitive impairment

To determine the relationship between psychological stress with cognitive outcomes in a multi-centre longitudinal study of people with amnestic mild cognitive impairment (aMCI) we assessed three parameters of psychological stress (Recent Life Changes Questionnaire (RLCQ); the Perceived Stress Scale (PSS) and salivary cortisol) and their relationship with rates of cognitive decline over an 18 month follow up period and conversion to dementia over a 5.5 year period. In 133 aMCI and 68 cognitively intact participants the PSS score was higher in the aMCI compared with control group but neither the RLCQ scores nor salivary cortisol measures were different between groups. In the aMCI group the RLCQ and the PSS showed no significant association with cognitive function at baseline, cognitive decline or with conversion rates to dementia but high salivary cortisol levels were associated with RLCQ scores and poorer cognitive function at baseline and lower rates of cognitive decline. No relationship was found between salivary cortisol levels and conversion rate to dementia. We conclude that psychological stress as measured by the RLCQ or PSS was not associated with adverse cognitive outcomes in an aMCI population and hypothesise that this may reflect diminished cortisol production to psychological stress as the disease progresses.</p

Periodontitis and cognitive decline in Alzheimer's disease.

Periodontitis is common in the elderly and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Elevated antibodies to periodontal bacteria are associated with an increased systemic pro-inflammatory state. Elsewhere raised serum pro-inflammatory cytokines have been associated with an increased rate of cognitive decline in Alzheimer's disease. We hypothesized that periodontitis would be associated with increased dementia severity and a more rapid cognitive decline in Alzheimer's disease. We aimed to determine if periodontitis in Alzheimer's disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. In a six month observational cohort study 60 community dwelling participants with mild to moderate Alzheimer's Disease were cognitively assessed and a blood sample taken for systemic inflammatory markers. Dental health was assessed by a dental hygienist, blind to cognitive outcomes. All assessments were repeated at six months. The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six month follow up period. Our data showed that periodontitis is associated with an increase in cognitive decline in Alzheimer's Disease, independent to baseline cognitive state, which may be mediated through effects on systemic inflammation

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Stress and its impact on cognition in mild cognitive impairment

Participants with amnestic Mild Cognitive Impairment (aMCI) do not inevitably show cognitive decline or convert to Alzheimer’s disease (AD) supporting the hypothesis that secondary events are crucial in the conversion process. Research suggests that psychological stress is a risk factor for AD. Therefore, we proposed psychological stress will be associated with worsened cognitive decline, a clinical marker of advancing neurodegeneration.This was a longitudinal observational study assessing the association between the degree of psychological stress and cognitive decline in 134 aMCI participants and 69 control participants. We hypothesised that stress, as measured by the Recent Life Change Questionnaire (RLCQ), would be associated with worsened cognitive decline, as measured by the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR), over an 18 month follow-up period. Other secondary cognitive outcomes included the difference in change of the Montreal Cognitive Assessment score and the Trail Making Test Part B. Exploratory measures of stress included the Perceived Stress Scale and the presence of physical stressors. Hypothesised modulators of the stress response were assessed including mood, neuroticism, social support, and favoured coping style. Biological outcomes included changes in blood levels of inflammatory markers and salivary cortisol.Objective stressful life events occurring during the course of the study were associated with increased rates of cognitive decline across a range of measures in the aMCI group. Whereas, as predicted, psychological stress was not associated with cognitive decline in the control group. Presence of the ApoE ε4 allele was associated with an increased rate of cognitive decline and increased serum levels of the anti-inflammatory cytokine TGFβ was associated with a slower rate of cognitive decline in the aMCI group. We found that neither measures of mood nor potential modulators of stress exerted a consistent significant influence over rates of cognitive decline in the aMCI group

Strategies to improve recruitment of people with dementia to research studies

Background: Low participation in research is one of the key challenges to advancing understanding of dementia, and improving the care and treatment of those who live with this condition. Nurses and nurse researchers play a vital role in recruiting people with dementia to studies, as several countries including the United States and the United Kingdom set national targets and develop initiatives to encourage more people with dementia to take part in research. Aim: To highlight the challenges to recruiting people with dementia to studies, and to identify strategies that nurses, and in particular, nurse researchers can use for overcoming them. Our focus is primarily on the role of nurses in recruiting people with dementia to dementia studies, but much of the discussion will apply to other health professionals involved in the recruitment of people with dementia to research more generally. Discussion: Challenges discussed include a lack of awareness about research participation opportunities and a suitable study partner. We discuss how the nurses’ role is to ensure that recruitment practices are personalised and responsive to participants’ needs and situation, rather than target-driven. The notion of responsible research is used to anchor the discussion.Conclusion: Increasing the participation of people with dementia in research is a global priority. Nurses and nurse researchers play an important role in ensuring that people who take part in research have an optimal research experience.Implications for practice: Recruiting people with dementia to research studies is a national priority in many countries. With a greater understanding of the challenges involved and strategies that can be used to overcome them, nurses can have an effective role in the recruitment process and research experience. <br/

Relationships between baseline serum inflammatory markers and baseline demographics; cognitive measures and dental health measures.

<p>Relationships between baseline serum inflammatory markers and baseline demographics; cognitive measures and dental health measures.</p

Relationships between the presence of periodontitis and baseline demographics, other dental health measures and cognitive scores.

<p>Relationships between the presence of periodontitis and baseline demographics, other dental health measures and cognitive scores.</p

Relationships between change in serum inflammatory markers from baseline and baseline dental health measures.

<p>Relationships between change in serum inflammatory markers from baseline and baseline dental health measures.</p