Age dependency of risk factors for cognitive decline.

BACKGROUND: Risk factors for cognitive decline might depend on chronological age. The aim of the study was to explore the age dependency of risk factors for cognitive decline in cognitively healthy subjects aged 55-85 years at baseline. METHODS: We included 2527 cognitively healthy subjects from the Longitudinal Aging Study Amsterdam (LASA). Median follow-up was 9.1 (IQR: 3.2-19.0) years. The association of genetic and cardiovascular risk factors, depressive symptoms, inflammation markers and lifestyle risk factors with decline in MMSE and memory function was tested using spline regression analyses. RESULTS: Subjects were on average 70.1 (SD 8.8) years old at baseline. Based on a spline regression model, we divided our sample in three age groups: ≤70 years (young-old), > 70-80 years (old) and > 80 years (oldest-old). The association of LDL cholesterol, homocysteine, hypertension, history of stroke, depressive symptoms, interleukin-6, a1-antichymotrypsin, alcohol use and smoking with cognitive decline significantly differed between the age groups. In general, the presence of these risk factors was associated with less cognitive decline in the oldest-old group compared to the young-old and old group. CONCLUSIONS: The negative effect of various risk factors on cognitive decline decreases with higher age. A combination of epidemiological factors, such as the selection towards healthier subjects during follow-up, but also risk factor specific features, for example ensuring the cerebral blood flow in case of hypertension, explain this diminished association at higher age. It is important to take these age differences into account when applying preventive strategies to avert cognitive decline.

Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'.

BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid ß peptide 1-42 (Aß42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Aß42 in the cerebrospinal fluid (Aß positive). Compared to the aMCI group with high Aß42 levels (Aß negative), Aß positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.

Coherent Excited States in Superconductors due to a Microwave Field.

We describe theoretically the depairing effect of a microwave field on diffusive s-wave superconductors. The ground state of the superconductor is altered qualitatively in analogy to the depairing due to a dc current. In contrast to dc depairing, the density of states acquires, for microwaves with frequency ω_{0}, steps at multiples of the photon energy Δ±nℏω_{0} and shows an exponential-like tail in the subgap regime. We show that this ac depairing explains the measured frequency shift of a superconducting resonator with microwave power at low temperatures.

The trajectory of cognitive decline in the pre-dementia phase in memory clinic visitors: findings from the 4C-MCI study.

BACKGROUND: We investigated the course of decline in multiple cognitive domains in non-demented subjects from a memory clinic setting, and compared pattern, onset and magnitude of decline between subjects who progressed to Alzheimer's disease (AD) dementia at follow-up and subjects who did not progress. METHOD: In this retrospective cohort study 819 consecutive non-demented patients who visited the memory clinics in Maastricht or Amsterdam between 1987 and 2010 were followed until they became demented or for a maximum of 10 years (range 0.5-10 years). Differences in trajectories of episodic memory, executive functioning, verbal fluency, and information processing speed/attention between converters to AD dementia and subjects remaining non-demented were compared by means of random effects modelling. RESULTS: The cognitive performance of converters and non-converters could already be differentiated seven (episodic memory) to three (verbal fluency and executive functioning) years prior to dementia diagnosis. Converters declined in these three domains, while non-converters remained stable on episodic memory and executive functioning and showed modest decline in verbal fluency. There was no evidence of decline in information processing speed/attention in either group. CONCLUSIONS: Differences in cognitive performance between converters to AD dementia and subjects remaining non-demented could be established 7 years prior to diagnosis for episodic memory, with verbal fluency and executive functioning following several years later. Therefore, in addition to early episodic memory decline, decline in executive functions may also flag incident AD dementia. By contrast, change in information processing speed/attention seems less informative.

Evidence of a nonequilibrium distribution of quasiparticles in the microwave response of a superconducting aluminum resonator.

In a superconductor, absorption of photons with an energy below the superconducting gap leads to redistribution of quasiparticles over energy and thus induces a strong nonequilibrium quasiparticle energy distribution. We have measured the electrodynamic response, quality factor, and resonant frequency of a superconducting aluminium microwave resonator as a function of microwave power and temperature. Below 200 mK, both the quality factor and resonant frequency decrease with increasing microwave power, consistent with the creation of excess quasiparticles due to microwave absorption. Counterintuitively, above 200 mK, the quality factor and resonant frequency increase with increasing power. We demonstrate that the effect can only be understood by a nonthermal quasiparticle distribution.

Validation, Deployment, and Real-World Implementation of a Modular Toolbox for Alzheimer's Disease Detection and Dementia Risk Reduction: The AD-RIDDLE Project.

The Real-World Implementation, Deployment, and Validation of Early Detection Tools and Lifestyle Enhancement (AD-RIDDLE) project, recently launched with the support of the EU Innovative Health Initiative (IHI) public-private partnership and UK Research and Innovation (UKRI), aims to develop, test, and deploy a modular toolbox platform that can reduce existing barriers to the timely detection, and therapeutic approaches in Alzheimer's disease (AD), thus accelerating AD innovation. By focusing on health system and health worker practices, AD-RIDDLE seeks to improve and smooth AD management at and between each key step of the clinical pathway and across the disease continuum, from at-risk asymptomatic stages to early symptomatic ones. This includes innovation and improvement in AD awareness, risk reduction and prevention, detection, diagnosis, and intervention. The 24 partners in the AD-RIDDLE interdisciplinary consortium will develop and test the AD-RIDDLE toolbox platform and its components individually and in combination in six European countries. Expected results from this cross-sectoral research collaboration include tools for earlier detection and accurate diagnosis; validated, novel digital cognitive and blood-based biomarkers; and improved access to individualized preventative interventions (including multimodal interventions and symptomatic/disease-modifying therapies) across diverse populations, within the framework of precision medicine. Overall, AD-RIDDLE toolbox platform will advance management of AD, improving outcomes for patients and their families, and reducing costs.

Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment.

BACKGROUND: Anxiety, apathy and depression are common in subjects with mild cognitive impairment (MCI) and may herald Alzheimer's disease (AD). We investigated whether these symptoms correlated with cerebrospinal fluid (CSF) markers for AD in subjects with MCI. Method Subjects with MCI (n=268) were selected from the 'Development of screening guidelines and criteria for pre-dementia Alzheimer's disease' (DESCRIPA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. We measured amyloid ß(1-42) protein (Aß42) and total tau (t-tau) in CSF. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory. RESULTS: Depressive symptoms were reported by 55 subjects (21%), anxiety by 35 subjects (13%) and apathy by 49 subjects (18%). The presence of anxiety was associated with abnormal CSF Aß42 [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6-3.3] and t-tau (OR 2.6, 95% CI 1.9-3.6) concentrations and with the combination of abnormal concentrations of both Aß42 and t-tau (OR 3.1, 95% CI 2.0-4.7). The presence of agitation and irritability was associated with abnormal concentrations of Aß42 (agitation: OR 1.6, 95% CI 1.1-2.3; irritability: OR 2.2, 95% CI 1.5-3.3). Symptoms of depression and apathy were not related to any of the CSF markers. CONCLUSIONS: In subjects with MCI, symptoms of anxiety, agitation and irritability may reflect underlying AD pathology, whereas symptoms of depression and apathy do not.

Combined Evidence for a Long-Term, Clinical Slowing Effect of Multinutrient Intervention in Prodromal Alzheimer's Disease: Post-Hoc Analysis of 3-Year Data from the LipiDiDiet Trial.

The LipiDiDiet randomized clinical trial is evaluating the long term effects of a multinutrient intervention (Fortasyn Connect) compared with control in participants with prodromal AD. In this post-hoc analysis we used the Alzheimer's Disease Composite Score (ADCOMS) as a measure of cognition and global function, together with a global statistical test (GST) and Bayesian hierarchical modelling (BHM) to evaluate the totality of evidence for an effect of the intervention over 36 months. The analysis includes 67 participants (39 active, 28 control) with change from baseline data after 36 months intervention. All outcome measures showed a statistically significant effect for the intervention: ADCOMS (P =0.045), GST (P <0.001), and BHM (P =0.008 based on 3 outcomes and P <0.001 including all primary and secondary quantitative clinical outcomes). Fortasyn Connect was associated with significantly less clinical decline over 36 months, suggesting the long-lasting beneficial effects of the multinutrient in prodromal AD.

Axonal damage and astrocytosis are biological correlates of grey matter network integrity loss: a cohort study in autosomal dominant Alzheimer disease.

Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aß, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes. Key points: Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions.The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD.Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.

Strongly disordered TiN and NbTiN s-wave superconductors probed by microwave electrodynamics.

We probe the effects of strong disorder (2.4

Increased risk of mortality associated with social isolation in older men: only when feeling lonely? Results from the Amsterdam Study of the Elderly (AMSTEL).

BACKGROUND: Loneliness has a significant influence on both physical and mental health. Few studies have investigated the possible associations of loneliness with mortality risk, impact on men and women and whether this impact concerns the situation of being alone (social isolation), experiencing loneliness (feeling lonely) or both. The current study investigated whether social isolation and feelings of loneliness in older men and women were associated with increased mortality risk, controlling for depression and other potentially confounding factors. METHOD: In our prospective cohort study of 4004 older persons aged 65-84 years with a 10-year follow-up of mortality data a Cox proportional hazard regression analysis was used to test whether social isolation factors and feelings of loneliness predicted an increased risk of mortality, controlling for psychiatric disorders and medical conditions, cognitive functioning, functional status and sociodemographic factors. RESULTS: At 10 years follow-up, significantly more men than women with feelings of loneliness at baseline had died. After adjustment for explanatory variables including social isolation, the mortality hazard ratio for feelings of loneliness was 1.30 [95% confidence interval (CI) 1.04-1.63] in men and 1.04 (95% CI 0.90-1.24) in women. No higher risk of mortality was found for social isolation. CONCLUSIONS: Feelings of loneliness rather than social isolation factors were found to be a major risk factor for increasing mortality in older men. Developing a better understanding of the nature of this association may help us to improve quality of life and longevity, especially in older men.

Model and Measurements of an Optical Stack for Broadband Visible to Near-Infrared Absorption in TiN MKIDs.

Typical materials for optical Microwave Kinetic Inductance Detetectors (MKIDs) are metals with a natural absorption of ∼ 30-50% in the visible and near-infrared. To reach high absorption efficiencies (90-100%) the KID must be embedded in an optical stack. We show an optical stack design for a 60 nm TiN film. The optical stack is modeled as sections of transmission lines, where the parameters for each section are related to the optical properties of each layer. We derive the complex permittivity of the TiN film from a spectral ellipsometry measurement. The designed optical stack is optimised for broadband absorption and consists of, from top (illumination side) to bottom: 85 nm SiO2, 60 nm TiN, 23 nm of SiO2, and a 100 nm thick Al mirror. We show the modeled absorption and reflection of this stack, which has >80% absorption from 400 to 1550 nm and near-unity absorption for 500-800 nm. We measure transmission and reflection of this stack with a commercial spectrophotometer. The results are in good agreement with the model.

Number fluctuations of sparse quasiparticles in a superconductor.

We have directly measured quasiparticle number fluctuations in a thin film superconducting Al resonator in thermal equilibrium. The spectrum of these fluctuations provides a measure of both the density and the lifetime of the quasiparticles. We observe that the quasiparticle density decreases exponentially with decreasing temperature, as theoretically predicted, but saturates below 160 mK to 25-55/µm(3). We show that this saturation is consistent with the measured saturation in the quasiparticle lifetime, which also explains similar observations in qubit decoherence times.

Regional differences in effects of APOE ε4 on cognitive impairment in non-demented subjects.

BACKGROUND: The APOE ε4 allele is a risk factor for Alzheimer's disease (AD). APOE ε4 is common in non-demented subjects with cognitive impairment. In both healthy people and people with AD, its prevalence has a north-south gradient across Europe. In the present study, we investigated whether the relation between the APOE ε4 allele and cognitive impairment varied across Northern, Middle and Southern Europe. We also investigated whether a north-south gradient existed in subjects with subjective cognitive impairment (SCI), amnestic mild cognitive impairment (MCI) and non-amnestic MCI. METHODS: Data from 16 centers across Europe were analyzed. RESULTS: A north-south gradient in APOE ε4 prevalence existed in the total sample (62.7% for APOE ε4 carriers in the northern region, 42.1% in the middle region, and 31.5% in the southern region) and in subjects with SCI and amnestic MCI separately. Only in Middle Europe was the APOE ε4 allele significantly associated with poor performance on tests of delayed recall and learning, as well as with the amnestic subtype of MCI. CONCLUSION: The APOE ε4 allele frequencies in subjects with SCI and amnestic MCI have a north-south gradient. The relation between the APOE ε4 allele and cognition is region dependent.

[The role of CSF markers in the early diagnosis of Alzheimer's disease]. / De rol van liquormarkers bij de vroege diagnostiek van de ziekte van Alzheimer.

BACKGROUND: Biomarkers in cerebrospinal fluid (CSF) are being used increasingly to diagnose early Alzheimer's disease (AD). A CSF profile that is suggestive of ad is an abnormal ratio of the proteins Ab1-42 to total tau. AIM: To describe the prevalence and prognosis of a CSF profile in patients without dementia but with subjective memory problems and mild cognitive impairments (MCI) at a memory clinic. METHOD: A multi-centre study. RESULTS: A European multi-centre study showed that a CSF AD profile was often present in patients with subjective complaints and patients with MCI . The CSF AD profile predicted a decline in cognition and daily functioning over a period of 3 years in patients with MCI. Patients with amnestic MCI and a CSF AD profile developed AD more often within this period than patients without this profile. CONCLUSION: CSF markers suggestive of ad are common in persons without dementia. It may be possible to use these markers for the prognosis of patients who have MCI .

Affective symptoms as predictors of Alzheimer's disease in subjects with mild cognitive impairment: a 10-year follow-up study.

BACKGROUND: Affective symptoms are common in subjects with mild cognitive impairment (MCI), but there is disagreement whether these symptoms are predictive for Alzheimer's disease (AD). We investigated the predictive accuracy of affective symptoms for AD during a follow-up study in subjects with MCI, and whether the predictive accuracy was modified by age, the presence of amnestic MCI or the length of follow-up. METHOD: Newly referred subjects (n=263) with MCI older than 55 years were selected from a memory clinic and followed up after 2, 5 and 10 years. Predictors investigated were: symptoms of depression, anxiety, apathy and sleeping problems. RESULTS: Affective symptoms were present in 50-70% of the subjects. The average follow-up period was 5.4 years and 79 subjects (29%) developed AD. Sleeping problems were associated with a decreased risk for AD [odds ratio (OR) 0.35, p<0.001]. Symptoms of depression (OR 0.61, p=0.059) and anxiety (OR 0.58, p=0.051) showed a trend in the same direction. The OR of apathy for AD was 0.67 (p=0.14). Depression was associated with a decreased risk for AD only in subjects without amnestic MCI, but not in subjects with amnestic MCI. Moreover, anxiety was related to the risk for AD differently between subjects diagnosed with AD at the 5-year follow-up (OR 0.23) and subjects diagnosed with AD at the 10-year follow-up (OR 1.7). CONCLUSIONS: Affective symptoms are associated with a decreased risk for AD. The risk may be dependent on MCI subtype or length of follow-up, but it does not depend on age.

The effect of the APOE-epsilon4 allele and ACE-I/D polymorphism on cognition during a two-year follow-up in first-ever stroke patients.

BACKGROUND: Cognitive impairment is commonly observed after stroke and has a negative impact on survival and rehabilitation. Some stroke patients deteriorate in cognitive functioning whereas others do not. Environmental and demographic risk factors cannot fully explain this. There is growing evidence that a genetic predisposition plays a role in the pathogenesis of post-stroke cognitive decline. OBJECTIVE: To study the influence of the APOE-epsilon4 allele and the ACE-I/D polymorphism on cognitive functioning after stroke. METHODS: We included 194 first-ever stroke patients of whom information about APOE genotyping and ACE-I/D polymorphism was available in 92 and 129 patients, respectively. Patients were cognitively assessed at 1, 6, 12 and 24 months after the event. Linear mixed models with slope estimates were used to study the influence of the APOE-epsilon4 allele and the ACE-I/D polymorphism on the MMSE score, CAMCOG, executive functioning, psychomotor speed, and verbal memory function during follow-up. RESULTS: Patients carrying the APOE-epsilon4 allele more often suffered a lacunar infarction than non-carriers. The APOE-epsilon4 allele had no effect on cognitive functioning during the follow-up. ACE-DD homozygosity was associated with a worse performance in executive functioning compared to patients with neither an APOE-epsilon4 allele nor the ACE-DD genotype. There was no interaction between the APOE-epsilon4 allele and the ACE-DD phenotype in the prediction of cognitive decline. CONCLUSION: The ACE-DD genotype may be associated with post-stroke cognitive decline while the APOE-epsilon4 allele is not. Further research is needed to examine the role of genetic risk factors for post-stroke cognitive decline and to determine why some patients deteriorate cognitively after stroke but others do not.

Microvascular changes of the retina in ankylosing spondylitis, and the association with cardiovascular disease - the eye for a heart study.

OBJECTIVE: Ankylosing spondylitis (AS) is associated with an increased risk of cardiovascular disease (CVD). Microvasculature changes can precede overt CVD, but have been studied poorly in AS. The retinal vasculature is easily accessible and changes are associated with CVD (e.g. arteriolar narrowing, venular widening, loss of tortuosity). This proof of concept study compared the retinal microvasculature of AS patients with healthy controls, and the influence of gender. METHODS: Cross-sectional case-control study comparing AS patients with healthy controls. Main inclusion criteria were: age 50-75 years, no diabetes mellitus and, for AS, fulfillment of the modified New York criteria. All subjects underwent fundus photography, analyzed with Singapore I Vessel Assessment software, and Optical Coherence Tomography Angiography (OCTA). Subjects were compared with generalized estimating equations (GEE). Multivariable analyses were adjusted for demographics and cardiovascular risk, and stratified for gender. RESULTS: Fifty-nine AS patients and 105 controls were included (50% women). Controls were significantly older than patients (68 versus 60, p<0.01), but did not differ in cardiovascular profile. Patients had a lower retinal arteriolar tortuosity (ß Ì¶-0.1, 95%CI [-0.2; -0.01], p = 0.02), and higher vessel density (ß 0.5, 95% CI [0.1; 0.9], p = 0.02). In addition, male AS patients showed a lower arteriovenular ratio compared to male controls (ß -0.03, p = 0.04, 95%CI [-0.05; -0.001]). There were no differences found between women with and without AS. CONCLUSION: This study detected several retinal microvascular changes, in AS patients compared to controls, which have been associated with CVD. Retinal imaging might be an interesting tool for future CVD screening.

White matter hyperintensities and medial temporal lobe atrophy in clinical subtypes of mild cognitive impairment: the DESCRIPA study.

BACKGROUND: Clinical subtypes of mild cognitive impairment (MCI) may represent different underlying aetiologies. METHODS: This European, multicentre, memory clinic based study (DESCRIPA) of non-demented subjects investigated whether MCI subtypes have different brain correlates on MRI and whether the relation between subtypes and brain pathology is modified by age. Using visual rating scales, medial temporal lobe atrophy (MTA) (0-4) and white matter hyperintensities (WMH) (0-30) were assessed. RESULTS: Severity of MTA differed between MCI subtypes (p<0.001), increasing from a mean of 0.8 (SD 0.7) in subjective complaints (n = 77) to 1.3 (0.8) in non-amnestic MCI (n = 93), and from 1.4 (0.9) in single domain amnestic MCI (n = 70) to 1.7 (0.9) in multiple domain amnestic MCI (n = 89). The association between MCI subtype and MTA was modified by age and mainly present in subjects >70 years of age. Severity of WMH did not differ between MCI subtypes (p = 0.21). However, the combination of MTA and WMH differed between MCI subtypes (p = 0.02) CONCLUSION: We conclude that MCI subtypes may have different brain substrates, especially in older subjects. Isolated MTA was mainly associated with amnestic MCI subtypes, suggesting AD as the underlying cause. In non-amnestic MCI, the relatively higher prevalence of MTA in combination with WMH may suggest a different pathophysiological origin.

Predictive value of mild cognitive impairment for dementia. The influence of case definition and age.

BACKGROUND/AIMS: In population studies, different mild cognitive impairment (MCI) definitions have been used to predict dementia at a later stage. This study compared predictive values of different MCI definitions for dementia, and the effect of age on the predictive values was investigated. METHODS: This study was conducted as part of an ongoing longitudinal study into the determinants of cognitive aging, the Maastricht Aging Study. RESULTS: MCI best predicted dementia when multiple cognitive domains were considered and subjective complaints were not (sensitivity: 0.66, specificity: 0.78). Age had a strong influence on the sensitivity of MCI for dementia (age 60-70 years: sensitivity = 0.56; age 70-85 years: sensitivity = 0.70). CONCLUSION: The inclusion of multiple cognitive domains and participants aged 70 years and older leads to the best prediction of dementia, regardless of subjective complaints.