The locus coeruleus (LC) supplies norepinephrine to the brain, is one of the first sites of tau deposition in Alzheimer's disease (AD) and modulates a variety of behaviors and cognitive functions. ...Transgenic mouse models showed that norepinephrine dysregulation after LC lesions exacerbates inflammatory responses, blood-brain barrier leakage (BBB), and cognitive deficits. Here, we investigated relationships between central norepinephrine metabolism, tau and beta-amyloid (Aβ), inflammation, BBB-dysfunction, neuropsychiatric problems, and memory in-vivo in a memory clinic population (total n = 111, 60 subjective cognitive decline, 36 mild cognitively impaired, and 19 AD dementia). Cerebrospinal fluid (CSF) and blood samples were collected and analyzed for 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), CSF/plasma albumin ratio (Q-alb), Aβ, phosphorylated tau, and interleukins. The verbal word learning task and the neuropsychiatric inventory assessed memory functioning and neuropsychiatric symptoms. Structural equation models tested the relationships between all fluid markers, cognition and behavior, corrected for age, education, sex, and clinical dementia rating score. Our results showed that neuropsychiatric symptoms show strong links to both MHPG and p-tau, whereas memory deficits are linked to MHPG via a combination of p-tau and inflammation-driven amyloidosis (30-35% indirect effect contribution). These results suggest that the LC-norepinephrine may be pivotal to understand links between AD pathology and behavioral and cognitive deficits in AD.
There has been increasing interest in finding non-invasive biomarkers for neurodegenerative diseases such as Alzheimer's disease (AD). This observational study investigated AD-specific biomarkers in ...tear fluid. Tear fluid was collected from a total of 65 subjects, including 23 patients with subjective cognitive decline (SCD), 22 patients with mild cognitive impairment (MCI), 11 dementia patients and 9 healthy controls (HC). Levels of amyloid-beta peptides (AB38, AB40, AB42), total-tau (t-tau) and phosphorylated-tau (p-tau) were determined using multiplex immunoassays. Levels of AB40 and t-tau were detectable in the vast majority (> 94%) of tear fluid samples. Cerebrospinal fluid (CSF) was available from a subset of patients. In this group, tear t-tau levels were significantly higher in people with dementia compared to SCD patients. Tear t-tau levels were elevated in patients with neurodegeneration (classified according to the A/T/N system) compared to patients without neurodegeneration. Negative correlations were found between CSF AB42 and CSF t-tau, and between CSF AB42 and tear t-tau. In summary, this study shows the potential of tau proteins in tear fluid to be associated with disease severity and neurodegeneration.
To examine trajectories of depression and apathy over a 5-year follow-up period in (prodromal) Alzheimer's disease (AD), and to relate these trajectories to AD biomarkers.
The trajectories of ...depression and apathy (measured with the Neuropsychiatric Inventory or its questionnaire) were separately modeled using growth mixture models for two cohorts (National Alzheimer's Coordinating Center, NACC, n = 22 760 and Alzheimer's Disease Neuroimaging Initiative, ADNI, n = 1 733). The trajectories in ADNI were associated with baseline CSF AD biomarkers (Aβ
t-tau, and p-tau) using bias-corrected multinomial logistic regression.
Multiple classes were identified, with the largest classes having no symptoms over time. Lower Aβ
and higher tau (ie, more AD pathology) was associated with increased probability of depression and apathy over time, compared to classes without symptoms. Lower Aβ
(but not tau) was associated with a steep increase of apathy, whereas higher tau (but not Aβ
) was associated with a steep decrease of apathy.
The trajectories of depression and apathy in individuals on the AD spectrum are associated with AD biomarkers.
Alzheimer's disease (AD) is the most common cause of dementia, and due to increasing life expectancy the number of patients is expected to grow. The diagnosis of AD involves the use of biomarkers ...determined by an amyloid PET scan or cerebrospinal fluid analyses that are either invasive or expensive, and not available in each hospital, thus limiting their usage as a front-line screener. The TearAD study aims to use tear fluid as a potential source for AD biomarkers. In previous reports, we demonstrated that AD biomarkers amyloid-beta and tau, are measurable in tear fluid and are associated with disease severity and neurodegeration. This study aims to validate previous results in a larger cohort and evaluate the diagnostic accuracy of tear biomarkers to discriminate between individuals with and without neurodegeneration as determined by hippocampal atrophy.
The TearAD study is an observational longitudinal multi-center study that will enroll 50 cognitively healthy controls, 50 patients with subjective cognitive decline, 50 patients with mild cognitive impairment and 50 patients with AD dementia from the memory clinic. Participants will be examined at baseline, after one year, and after two years follow-up. Study assessments include neuropsychological tests and ophthalmic examination. All participants will receive a MRI scan, and a subset of the study population will undergo cerebral spinal fluid collection and an amyloid PET scan. Tear fluid will be collected with Schirmer strips and levels of Aβ38, Aβ40, Aβ42, t-tau and p-tau in tear fluid will be determined using multiplex immunoassays. Blood samples will be collected from all participants. Images of the retina will be obtained with a standard, hyperspectral and ultra-wide field fundus camera. Additionally, macular pigment optical density will be measured with the macular pigment reflectometer, and cross-sectional images of the retina will be obtained through optical coherence tomography imaging.
The TearAD study will provide insight into the potential diagnostic use of tear biomarkers as a minimally invasive and low cost tool for the screening and diagnosis of AD.
Retrospectively registered at clinicaltrials.gov (NCT05655793).
The identification of subjects with mild cognitive impairment (MCI) at high risk for Alzheimer's disease (AD) is important for prognosis and early intervention. The APOE-ε4 allele is the strongest ...known genetic risk factor for AD. The authors performed a meta-analysis to establish the predictive accuracy of the APOE-ε4 allele for progression from MCI to AD-type dementia.
The authors included 35 prospective cohort studies of subjects with MCI, including 6095 subjects, of whom 1236 progressed to AD-type dementia after 2.9 years of follow-up. Pooled estimates of the OR, sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratios (LR+ and LR-) were obtained using random-effects models.
The OR for subjects with MCI who are carriers of APOE-ε4 allele to progress to AD-type dementia was 2.29 (95% CI 1.88 to 2.80), the sensitivity was 0.53 (95% CI 0.46 to 0.61), the specificity was 0.67 (95% CI 0.62 to 0.71), the PPV was 0.57 (95% CI 0.48 to 0.66), the NPV was 0.75 (95% CI 0.70 to 0.80), the LR+ was 1.60 (95% CI 1.48 to 1.72), and the LR- was 0.75 (95% CI 0.67 to 0.82). Meta-regression showed that sensitivity, specificity and NPV were dependent on age, APOE-ε4 allele background prevalence or follow-up length.
The APOE-ε4 allele is associated with a moderately increased risk for progression from MCI to AD-type dementia. The low sensitivity and PPV makes genotyping of limited value for predicting AD-type dementia in clinical practice. For trials aiming to prevent progression from MCI to AD-type dementia, APOE genotyping may be useful in selecting subjects with a higher risk for progression to AD-type dementia.
Aims/hypothesis
Studies investigating associations between kynurenines and cognitive function have generally been small, restricted to clinical samples or have found inconsistent results, and ...associations in the general adult population, and in individuals with type 2 diabetes in particular, are not clear. Therefore, the aim of the present study was to investigate cross-sectional associations between plasma kynurenines and cognitive function in a cohort of middle-aged participants with normal glucose metabolism, prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes.
Methods
Plasma kynurenines were quantified in 2358 participants aged 61 ± 8 years. Cross-sectional associations of kynurenines with cognitive impairment and cognitive domain scores were investigated using logistic, multiple linear and restricted cubic spline regression analyses adjusted for several confounders.
Results
Effect modification by glucose metabolism status was found for several associations with cognitive impairment, hence analyses were stratified. In individuals with prediabetes, 3-hydroxykynurenine (OR per SD 0.59 95% CI 0.37, 0.94) and 3-hydroxyanthranilic acid (0.67 0.47, 0.96) were associated with lower odds of cognitive impairment after full adjustment. In individuals with type 2 diabetes, kynurenine (0.80 0.66, 0.98), 3-hydroxykynurenine (0.82 0.68, 0.99), kynurenic acid (0.81 0.68, 0.96), xanthurenic acid (0.73 0.61, 0.87) and 3-hydroxyanthranilic acid (0.73 0.60, 0.87) were all associated with lower odds of cognitive impairment. Kynurenic acid (β per SD 0.07 95% CI 0.02, 0.13) and xanthurenic acid (0.06 0.01, 0.11) were also associated with better executive function/attention. No associations were observed in individuals with normal glucose metabolism.
Conclusions/interpretation
Several kynurenines were cross-sectionally associated with lower odds of cognitive impairment and better cognitive functioning in type 2 diabetes, while less widespread associations were seen in prediabetes. Low levels of kynurenines might be involved in the pathway of type 2 diabetes and cognitive decline but this needs further studies.
Graphical abstract
To investigate the relationship between Alzheimer's disease biomarkers and neuropsychiatric symptoms.
Data from two large cohort studies, the Dutch Parelsnoer Institute - Neurodegenerative Diseases ...and the Alzheimer's Disease Neuroimaging Initiative was used, including subjects with subjective cognitive decline (N = 650), mild cognitive impairment (N = 887), and Alzheimer's disease dementia (N = 626). Cerebrospinal fluid (CSF) levels of Aβ
, t-tau, p-tau, and hippocampal volume were associated with neuropsychiatric symptoms (measured with the Neuropsychiatric Inventory) using multiple logistic regression analyses. The effect of the Mini-Mental State Examination (as proxy for cognitive functioning) on these relationships was assessed with mediation analyses.
Alzheimer's disease biomarkers were not associated with depression, agitation, irritability, and sleep disturbances. Lower levels of CSF Aβ
, higher levels of t- and p-tau were associated with presence of anxiety. Lower levels of CSF Aβ
and smaller hippocampal volumes were associated with presence of apathy. All associations were mediated by cognitive functioning.
The association between Alzheimer's disease pathology and anxiety and apathy is partly due to impairment in cognitive functioning.
Purpose
The Quality of Life Alzheimer’s Disease Scale (QoL-AD) is commonly used to assess disease specific health-related quality of life (HRQoL) as rated by patients and their carers. For ...cost-effectiveness analyses, utilities based on the EQ-5D are often required. We report a new mapping algorithm to obtain EQ-5D indices when only QoL-AD data are available.
Methods
Different statistical models to estimate utility directly, or responses to individual EQ-5D questions (response mapping) from QoL-AD, were trialled for patient-rated and proxy-rated questionnaires. Model performance was assessed by root mean square error and mean absolute error.
Results
The response model using multinomial regression including age and sex, performed best in both the estimation dataset and an independent dataset.
Conclusions
The recommended mapping algorithm allows researchers for the first time to estimate EQ-5D values from QoL-AD data, enabling cost-utility analyses using datasets where the QoL-AD but no utility measures were collected.
•The AD biomarker - affective symptoms relationship shows inconsistent evidence.•Study designs assessing this relationship are very heterogeneous.•Majority of studies on depression show no ...relationship with AT(N) markers.•Future research should focus on possible subtypes of affective symptoms.
Alzheimer’s disease (AD) biomarkers such as amyloid, p-tau and neuronal injury markers have been associated with affective symptoms in cognitively impaired individuals, but results are conflicting.
CINAHL, Embase, PsycINFO and PubMed were searched for studies evaluating AD biomarkers with affective symptoms in mild cognitive impairment and AD dementia. Studies were classified according to AT(N) research criteria.
Forty-five abstracts fulfilled eligibility criteria, including in total 8,293 patients (41 cross-sectional studies and 7 longitudinal studies). Depression and night-time behaviour disturbances were not related to AT(N) markers. Apathy was associated with A markers (PET, not CSF). Mixed findings were reported for the association between apathy and T(N) markers; anxiety and AT(N) markers; and between agitation and irritability and A markers. Agitation and irritability were not associated with T(N) markers.
Whereas some AD biomarkers showed to be associated with affective symptoms in AD, most evidence was inconsistent. This is likely due to differences in study design or heterogeneity in affective symptoms. Directions for future research are given.
Affective symptoms are considered a risk factor or prodromal symptom for dementia. Recent reviews indicate that depressive symptoms predict progression from mild cognitive impairment (MCI) to ...dementia, but results need to be further explored.
To investigate the effect of depressive symptoms on the development of dementia in people with MCI, and explore potential sources of between-study variability, including study setting by a systematic review and meta-analysis.
Databases were searched for prospective studies defining people with MCI at baseline, investigating dementia at follow-up and giving information about depressive symptoms. Two authors independently extracted data from the studies and rated the methodological quality. Meta-analyses were conducted using random-effect models to yield pooled risk ratios (RR). Meta-regression analyses tested differences between clinical and community-based studies and other sources of heterogeneity.
Thirty-five studies, representing 14,158 individuals with MCI, were included in the meta-analysis. Depressive symptoms in MCI predicted dementia in 15 community-based studies (RR = 1.69, 95% CI 1.49-1.93, I2 = 0.0%), but not in 20 clinical studies (RR = 1.02, 95% CI 0.92-1.14, I2 = 73.0%). Further investigation of this effect showed that the mean age of community-based studies was significantly higher than of clinical studies but neither this nor other study characteristics explained variability in study outcomes.
Depressive symptoms are associated with an increased risk of conversion from MCI to dementia in community-based studies. In contrast, evidence in clinical populations was insufficient with high heterogeneity.
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