Depressive Symptoms and Plasma Markers of Alzheimer's Disease and Neurodegeneration: A Coordinated Meta-Analysis of 8 Cohort Studies.

BACKGROUND: Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD). There has been a recent emergence in plasma biomarkers for AD pathophysiology, such as amyloid-beta (Aß) and phosphorylated tau (p-tau), as well as for axonal damage (neurofilament light, NfL) and astrocytic activation (glial fibrillary acidic protein, GFAP). Hypothesizing that depressive symptoms may occur along the AD process, we investigated associations between plasma biomarkers of AD with depressive symptoms in individuals without dementia. METHODS: A two-stage meta-analysis was performed on 2 clinic-based and 6 population-based cohorts (N = 7210) as part of the Netherlands Consortium of Dementia Cohorts. Plasma markers (Aß42/40, p-tau181, NfL, and GFAP) were measured using Single Molecular Array (Simoa; Quanterix) assays. Depressive symptoms were measured with validated questionnaires. We estimated the cross-sectional association of each standardized plasma marker (determinants) with standardized depressive symptoms (outcome) using linear regressions, correcting for age, sex, education, and APOE ε4 allele presence, as well as subgrouping by sex and APOE ε4 allele. Effect estimates were entered into a random-effects meta-analysis. RESULTS: Mean age of participants was 71 years. The prevalence of clinically relevant depressive symptoms ranged from 1% to 22%. None of the plasma markers were associated with depressive symptoms in the meta-analyses. However, NfL was associated with depressive symptoms only in APOE ε4 carriers (ß 0.11; 95% CI: 0.05-0.17). CONCLUSIONS: Late-life depressive symptoms did not show an association to plasma biomarkers of AD pathology. However, in APOE ε4 allele carriers, a more profound role of neurodegeneration was suggested with depressive symptoms.

Association of amyloid-beta with depression or depressive symptoms in older adults without dementia: a systematic review and meta-analysis.

Several lines of evidence have indicated that depression might be a prodromal symptom of Alzheimer's disease (AD). This systematic review and meta-analysis investigated the cross-sectional association between amyloid-beta, one of the key pathologies defining AD, and depression or depressive symptoms in older adults without dementia. A systematic search in PubMed yielded 689 peer-reviewed articles. After full-text screening, nine CSF studies, 11 PET studies, and five plasma studies were included. No association between amyloid-beta and depression or depressive symptoms were found using cerebrospinal fluid (CSF) (0.15; 95% CI: -0.08; 0.37), positron emission topography (PET) (Cohen's d: 0.09; 95% CI: -0.05; 0.24), or plasma (-0.01; 95% CI: -0.23; 0.22). However, subgroup analyses revealed an association in plasma studies of individuals with cognitive impairment. A trend of an association was found in the studies using CSF and PET. This systematic review and meta-analysis suggested that depressive symptoms may be part of the prodromal stage of dementia.

A taxonomy of threat and soothing influences in rheumatic and musculoskeletal diseases and central sensitivity syndromes.

Background: An imbalance in affect regulation, reflected by a hyperactive threat system and hypoactive soothing system, may impact physical symptoms in people with rheumatic and musculoskeletal diseases (RMD) and central sensitivity syndromes (CSS), including chronic fatigue syndrome, fibromyalgia, and irritable bowel syndrome. This study aimed to identify and structure comprehensive overviews of threat and soothing influences that may worsen or alleviate physical symptoms in people with RMD or CSS. Method: A concept mapping procedure was used. An online open-question survey (N = 686, 641 [93.4%] women) yielded comprehensive sets of 40 threats and 40 soothers that were individually sorted by people with RMD or CSS (N = 115, 112 [97.4%] women). Results: Hierarchical cluster analyses generated eight threat clusters: environmental stimuli, physical symptoms, food and drugs, inactivity, demands, effort, invalidation, and emotional stress. Ten soother clusters were identified: social emotional support, rest and balance, pleasant surroundings, illness understanding, positive mindset and autonomy, spirituality, leisure activity, wellness, treatment and care, and nutrition and treats. Conclusions: Our study provided a comprehensive taxonomy of threats and soothers in people with RMD or CSS. The results can be used in experimental research to label threat and soothing stimuli and in clinical practice to screen and monitor relevant treatment targets.

Plasma Markers of Alzheimer's Disease Pathology, Neuronal Injury, and Astrocytic Activation and MRI Load of Vascular Pathology and Neurodegeneration: The SMART-MR Study.

BACKGROUND: Two of the main causes for dementia are Alzheimer's disease (AD) and vascular pathology, with most patients showing mixed pathology. Plasma biomarkers for Alzheimer's disease-related pathology have recently emerged, including Aß (amyloid-beta), p-tau (phosphorylated tau), NfL (neurofilament light), and GFAP (glial fibrillary acidic protein). There is a current gap in the literature regarding whether there is an association between these plasma biomarkers with vascular pathology and neurodegeneration. METHODS AND RESULTS: Cross-sectional data from 594 individuals (mean [SD] age: 64 [8] years; 17% female) were included from the SMART-MR (Second Manifestations of Arterial Disease-Magnetic Resonance) study, a prospective cohort study of individuals with a history of arterial disease. Plasma markers were assessed using single molecular array assays (Quanterix). Magnetic resonance imaging markers included white matter hyperintensity volume, presence of infarcts (yes/no), total brain volume, and hippocampal volume assessed on 1.5T magnetic resonance imaging. Linear regressions were performed for each standardized plasma marker with white matter hyperintensity volume, total brain volume, and hippocampal volume as separate outcomes, correcting for age, sex, education, and intracranial volume. Logistic regressions were performed for the presence of lacunar and cortical infarcts. Higher p-tau181 was associated with larger white matter hyperintensity volume (b per SD increase=0.16 [95% CI, 0.06-0.26], P=0.015). Higher NfL (b=-5.63, [95% CI, -8.95 to -2.31], P=0.015) was associated with lower total brain volume and the presence of infarcts (odds ratio [OR], 1.42 [95% CI, 1.13-1.78], P=0.039). Higher GFAP levels were associated with cortical infarcts (OR, 1.45 [95% CI, 1.09-1.92], P=0.010). CONCLUSIONS: Plasma biomarkers that have been associated with tau pathology, axonal injury, and astrocytic activation are related to magnetic resonance imagingmarkers of vascular pathology and neurodegeneration in patients with manifest arterial disease.