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.

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.

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.

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.

Alzheimer's Disease Composite Score: A Post-Hoc Analysis Using Data from the LipiDiDiet Trial in Prodromal Alzheimer's Disease.

As research evolves in prodromal AD, the need to validate sufficiently sensitive outcome measures, e.g. the Alzheimer's Disease Composite Score (ADCOMS) is clear. In the LipiDiDiet randomized trial in prodromal AD, cognitive decline in the study population was much less than expected in the timeframe studied. While the primary composite endpoint was insufficiently sensitive to detect a difference in the modified intention to treat population, the per-protocol population showed less decline in the active than the control group, indicating better treatment effects with regular product intake. These results were further strengthened by significant benefits on secondary endpoints of cognition and function, and brain atrophy. The present post-hoc analysis investigated whether ADCOMS could detect a difference between groups in the LipiDiDiet population (138 active, 140 control). The estimated mean change in ADCOMS from baseline (standard error) was 0.085 (0.018) in the active and 0.133 (0.018) in the control group; estimated mean treatment difference -0.048 (95% confidence intervals -0.090, -0.007; p=0.023), or 36% less decline in the active group. This suggests ADCOMS identified the cognitive and functional benefits observed previously, confirming the sensitivity of this composite measure.

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.

Functional and effective whole brain connectivity using magnetoencephalography to identify monozygotic twin pairs.

Resting-state functional connectivity patterns are highly stable over time within subjects. This suggests that such 'functional fingerprints' may have strong genetic component. We investigated whether the functional (FC) or effective (EC) connectivity patterns of one monozygotic twin could be used to identify the co-twin among a larger sample and determined the overlap in functional fingerprints within monozygotic (MZ) twin pairs using resting state magnetoencephalography (MEG). We included 32 cognitively normal MZ twin pairs from the Netherlands Twin Register who participate in the EMIF-AD preclinAD study (average age 68 years). Combining EC information across multiple frequency bands we obtained an identification rate over 75%. Since MZ twin pairs are genetically identical these results suggest a high genetic contribution to MEG-based EC patterns, leading to large similarities in brain connectivity patterns between two individuals even after 60 years of life or more.

Cognitive functioning of individuals aged 90 years and older without dementia: A systematic review.

INTRODUCTION: Reference values to define cognitive impairment in individuals aged 90 years and older are lacking. We systematically reviewed the literature to determine the level of cognitive functioning of individuals aged 90 years and older without dementia. METHODS: The search identified 3972 articles of which 20 articles were included in the review. We calculated mean cognitive test scores and cut-off scores for cognitive tests published in two or more articles. RESULTS: The mean cognitive test scores (SD)/cut-off scores for individuals aged 90 years and older without dementia of the five most commonly used cognitive tests were: MMSE: 26.6 (2.6)/23.3 points, Digit Span forward: 5.9 (1.8)/3.6 digits, Digit Span backward: 4.4 (1.6)/2.4 digits, TMT-A: 85.8 (42.5)/140.2s and TMT-B: 220.3 (99.2)/347.3s. DISCUSSION: We provided mean cognitive test scores and cut-off scores that will improve the diagnostic process of cognitive impairment in individuals aged 90 years and older.

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.

[Are the prevalence and incidence of dementia declining?]. / Nemen de prevalentie en incidentie van dementie af?

The Framingham Heart Study showed a 35 per cent drop in new dementia cases in 25 years from the late 1970s to the early 2010s. The question that has been asked is: can we stop worrying about the dementia pandemic? We argue that dementia will remain a major health problem. In the Framingham Heart Study the largest decrease in incidence occurred in the early nineties and levelled off in later years. Higher educational levels and improved cardiovascular risk management may explain part of the decreased incidence. The latter justifies intensive treatment of cardiovascular risk factors. This may have to start at an earlier age than is currently the case since hypertension, obesity and diabetes are now prevalent at younger ages. Despite the decrease in dementia incidence, the absolute numbers of people with dementia will increase due to the aging population. Research on early diagnosis and new treatments for dementia therefore remains crucial.

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.

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.

Fluctuations in the electron system of a superconductor exposed to a photon flux.

In a superconductor, in which electrons are paired, the density of unpaired electrons should become zero when approaching zero temperature. Therefore, radiation detectors based on breaking of pairs promise supreme sensitivity, which we demonstrate using an aluminium superconducting microwave resonator. Here we show that the resonator also enables the study of the response of the electron system of the superconductor to pair-breaking photons, microwave photons and varying temperatures. A large range in radiation power (at 1.54 THz) can be chosen by carefully filtering the radiation from a blackbody source. We identify two regimes. At high radiation power, fluctuations in the electron system caused by the random arrival rate of the photons are resolved, giving a straightforward measure of the optical efficiency (48 ± 8%) and showing an unprecedented detector sensitivity. At low radiation power, fluctuations are dominated by excess quasiparticles, the number of which is measured through their recombination lifetime.

Sensitivity of different MRI-techniques to assess gray matter atrophy patterns in Alzheimer's disease is region-specific.

The present study compares four different structural magnetic resonance imaging techniques used to measure gray matter (GM) atrophy in Alzheimer's disease (AD): manual and automated volumetry, cortical thickness (CT) and voxel-based morphometry (VBM). These techniques are used interchangeably in AD research and thus far it is unclear which technique is superior in detecting abnormalities early in the disease process. 18 healthy participants without any memory impairment, 18 patients with MCI, and 17 patients with mild AD were included and between-group differences were investigated in AD signature regions (areas in the prefrontal cortex (PFC), medial temporal lobe (MTL) and posterior parietal cortex (PPC)). Both manual volumetric measurements and VBM were able to detect GM atrophy in the early stages (differentiation controls and MCI), mainly in the MTL. In the early phase, automated volumetric measurements showed GM differences in the PPC but not in the MTL. In our sample, CT measurements were not sensitive for group differences in the early stages. PFC regions showed abnormalities in the later stages (controls vs AD) when manual volumetric measurements or VBM are employed. Manual volumetric measurements together with VBM are preferred techniques for assessing GM differences showing abnormalities in most of the investigated regions, with a predominance of the MTL in the early phase. Automated FreeSurfer volumetric measurements show similar performances in the early phase, displaying group differences in the PPC but not in MTL regions. Measurements of CT are less sensitive in the MCI stage and its sensitivity is restricted to the MTL and PPC regions in later stages of the disease (AD).

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.

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

We probe the effects of strong disorder (2.4

Age and diagnostic performance of Alzheimer disease CSF biomarkers.

OBJECTIVES: Core CSF changes in Alzheimer disease (AD) are decreased amyloid ß(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. METHODS: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis. RESULTS: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. CONCLUSION: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

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.