Plasma amyloid beta X-42/X-40 ratio and cognitive decline in suspected early and preclinical Alzheimer's disease.

INTRODUCTION: Blood-based biomarkers are a cost-effective and minimally invasive method for diagnosing the early and preclinical stages of amyloid positivity (AP). Our study aims to investigate our novel immunoprecipitation-immunoassay (IP-IA) as a test for predicting cognitive decline. METHODS: We measured levels of amyloid beta (Aß)X-40 and AßX-42 in immunoprecipitated eluates from the DELCODE cohort. Receiver-operating characteristic (ROC) curves, regression analyses, and Cox proportional hazard regression models were constructed to predict AP by Aß42/40 classification in cerebrospinal fluid (CSF) and conversion to mild cognitive impairment (MCI) or dementia. RESULTS: We detected a significant correlation between AßX-42/X-40 in plasma and CSF (r = 0.473). Mixed-modeling analysis revealed a substantial prediction of AßX-42/X-40 with an area under the curve (AUC) of 0.81 for AP (sensitivity: 0.79, specificity: 0.74, positive predictive value [PPV]: 0.71, negative predictive value [NPV]: 0.81). In addition, lower AßX-42/X-40 ratios were associated with negative PACC5 slopes, suggesting cognitive decline. DISCUSSION: Our results suggest that assessing the plasma AßX-42/X-40 ratio via our semiautomated IP-IA is a promising biomarker when examining patients with early or preclinical AD. HIGHLIGHTS: New plasma Aß42/Aß40 measurement using immunoprecipitation-immunoassay Plasma Aß42/Aß40 associated with longitudinal cognitive decline Promising biomarker to detect subjective cognitive decline at-risk for brain amyloid positivity.

Resting-State Network Alterations Differ between Alzheimer's Disease Atrophy Subtypes.

Several Alzheimer's disease (AD) atrophy subtypes were identified, but their brain network properties are unclear. We analyzed data from two independent datasets, including 166 participants (103 AD/63 controls) from the DZNE-longitudinal cognitive impairment and dementia study and 151 participants (121 AD/30 controls) from the AD neuroimaging initiative cohorts, aiming to identify differences between AD atrophy subtypes in resting-state functional magnetic resonance imaging intra-network connectivity (INC) and global and nodal network properties. Using a data-driven clustering approach, we identified four AD atrophy subtypes with differences in functional connectivity, accompanied by clinical and biomarker alterations, including a medio-temporal-predominant (S-MT), a limbic-predominant (S-L), a diffuse (S-D), and a mild-atrophy (S-MA) subtype. S-MT and S-D showed INC reduction in the default mode, dorsal attention, visual and limbic network, and a pronounced reduction of "global efficiency" and decrease of the "clustering coefficient" in parietal and temporal lobes. Despite severe atrophy in limbic areas, the S-L exhibited only marginal global network but substantial nodal network failure. S-MA, in contrast, showed limited impairment in clinical and cognitive scores but pronounced global network failure. Our results contribute toward a better understanding of heterogeneity in AD with the detection of distinct differences in functional connectivity networks accompanied by CSF biomarker and cognitive differences in AD subtypes.

[The Cost of Early Diagnosis of Cognitive Decline in German Memory Clinics]. / Kosten der Diagnostik kognitiver Störungen in deutschen Gedächtnisambulanzen.

Dementias are expensive diseases: the net annual cost in European healthcare is about € 28.000 per case with a strong stage dependency, of which medical care accounts for about 19%. Diagnostic costs, on the other hand, account for only a small proportion of the total costs. With changes in the guidelines, biomarker tests are becoming increasingly important. At present, the concrete economic impact of biomarker-based diagnosis is largely unknown. To determine the actual costs of diagnostic procedures based on guidelines, we conducted a survey among the members of the German Memory Clinic Network (DNG). From 15 expert centres, the staff engagement time for all procedures was collected. Based on the individual engagement times of the different professions, the total of personnel costs for diagnostics was calculated using current gross personnel costs. The total sum of diagnostic costs (personnel plus procedures) was calculated for three different scenarios e. g. € 633,97 for diagnostics without biomarkers, € 1.214,90 for diagnostics with CSF biomarkers and € 4.740,58 € for diagnostics with FDG- plus Amyloid-PET. In addition, the actual diagnostic costs of the current practice in expert memory clinics were estimated, taking into account personnel costs, costs for the different procedures and the frequency of their use across all patients. This results in total average costs of € 1.394,43 per case as the mean across all centres (personnel costs € 351,72, costs for diagnostic procedures € 1.042,71). The results show that state-of-the-art diagnosis of dementia and pre-dementia states, such as mild cognitive impairment (MCI) requires financial resources, which are currently not fully reimbursed in Germany. The need for a biomarker-based etiological diagnosis of dementia and pre-dementia states will increase, due to availability of disease-modifying treatments. Therefore, the current gap of reimbursement must be filled by new models of compensation.

Fornix fractional anisotropy mediates the association between Mediterranean diet adherence and memory four years later in older adults without dementia.

Here, we investigated whether fractional anisotropy (FA) of hippocampus-relevant white-matter tracts mediates the association between baseline Mediterranean diet adherence (MeDiAd) and verbal episodic memory over four years. Participants were healthy older adults with and without subjective cognitive decline and patients with amnestic mild cognitive impairment from the DELCODE cohort study (n = 376; age: 71.47 ± 6.09 years; 48.7 % female). MeDiAd and diffusion data were obtained at baseline. Verbal episodic memory was assessed at baseline and four yearly follow-ups. The associations between baseline MeDiAd and white matter, and verbal episodic memory's mean and rate of change over four years were tested with latent growth curve modeling. Baseline MeDiAd was associated with verbal episodic memory four years later (95 % confidence interval, CI [0.01, 0.32]) but not with its rate of change over this period. Baseline Fornix FA mediated - and, thus, explained - that association (95 % CI [0.002, 0.09]). Fornix FA may be an appropriate response biomarker of Mediterranean diet interventions on verbal memory in older adults.

Symptomatic Clusters Related to Amyloid Positivity in Cognitively Unimpaired Individuals.

Background: The NIA-AA Research Framework on Alzheimer's disease (AD) proposes a transitional stage (stage 2) characterized by subtle cognitive decline, subjective cognitive decline (SCD) and mild neurobehavioral symptoms (NPS). Objective: To identify participant clusters based on stage 2 features and assess their association with amyloid positivity in cognitively unimpaired individuals. Methods: We included baseline data of N = 338 cognitively unimpaired participants from the DELCODE cohort with data on cerebrospinal fluid biomarkers for AD. Classification into the AD continuum (i.e., amyloid positivity, A+) was based on Aß42/40 status. Neuropsychological test data were used to assess subtle objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPS. A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analyzed. Results: We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6%) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6%) and a cluster of participants with overall few symptoms (A+:19.7%) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aß42/ptau181 ratio compared to those with neither SCD nor OBJ. Conclusions: The cluster characterized by participants with OBJ and concomitant SCD was enriched for amyloid pathology.

A Residual Marker of Cognitive Reserve Is Associated with Resting-State Intrinsic Functional Connectivity Along the Alzheimer's Disease Continuum.

BACKGROUND: Cognitive reserve (CR) explains inter-individual differences in the impact of the neurodegenerative burden on cognitive functioning. A residual model was proposed to estimate CR more accurately than previous measures. However, associations between residual CR markers (CRM) and functional connectivity (FC) remain unexplored. OBJECTIVE: To explore the associations between the CRM and intrinsic network connectivity (INC) in resting-state networks along the neuropathological-continuum of Alzheimer's disease (ADN). METHODS: Three hundred eighteen participants from the DELCODE cohort were stratified using cerebrospinal fluid biomarkers according to the A(myloid-ß)/T(au)/N(eurodegeneration) classification. CRM was calculated utilizing residuals obtained from a multilinear regression model predicting cognition from markers of disease burden. Using an independent component analysis in resting-state fMRI data, we measured INC of resting-state networks, i.e., default mode network (DMN), frontoparietal network (FPN), salience network (SAL), and dorsal attention network. The associations of INC with a composite memory score and CRM and the associations of CRM with the seed-to-voxel functional connectivity of memory-related were tested in general linear models. RESULTS: CRM was positively associated with INC in the DMN in the entire cohort. The A+T+N+ group revealed an anti-correlation between the SAL and the DMN. Furthermore, CRM was positively associated with anti-correlation between memory-related regions in FPN and DMN in ADN and A+T/N+. CONCLUSION: Our results provide evidence that INC is associated with CRM in ADN defined as participants with amyloid pathology with or without cognitive symptoms, suggesting that the neural correlates of CR are mirrored in network FC in resting-state.

Lifelong experiences as a proxy of cognitive reserve moderate the association between connectivity and cognition in Alzheimer's disease.

Alzheimer's disease (AD) is associated with alterations in functional connectivity (FC) of the brain. The FC underpinnings of CR, that is, lifelong experiences, are largely unknown. Resting-state FC and structural MRI were performed in 76 CSF amyloid-ß (Aß) negative healthy controls and 152 Aß positive individuals as an AD spectrum cohort (ADS; 55 with subjective cognitive decline, SCD; 52 with mild cognitive impairment; 45 with AD dementia). Following a region-of-interest (ROI) FC analysis, intrinsic network connectivity within the default-mode network (INC-DMN) and anti-correlation in INC between the DMN and dorsal attention network (DMN:DAN) were obtained as composite scores. CR was estimated by education and Lifetime Experiences Questionnaire (LEQ). The association between INC-DMN and MEM was attenuated by higher LEQ scores in the entire ADS group, particularly in SCD. In ROI analyses, higher LEQ scores were associated with higher FC within the DMN in ADS group. INC-DMN remains relatively intact despite memory decline in individuals with higher lifetime activity estimates, supporting a role for functional networks in maintaining cognitive function in AD.

Safety and efficacy of plasma transfusion from exercise-trained donors in patients with early Alzheimer's disease: protocol for the ExPlas study.

INTRODUCTION: Given that exercise training reduces the risk of developing Alzheimer's disease (AD), induces changes in the blood composition and has widespread systemic benefits, it is reasonable to hypothesise that exercised plasma (ExPlas) may have rejuvenative properties. The main objective is to test safety and tolerability of transfusing ExPlas from young, healthy, fit adults to patients with mild cognitive impairment (MCI) or early AD. The study is a pilot for a future efficacy study. The key secondary objectives are examining the effect of plasma transfusions on cognitive function, fitness level, vascular risk profile, assessment of cerebral blood flow and hippocampal volume, quality of life, functional connectivity assessed by resting state functional MRI and biomarkers in blood and cerebrospinal fluid. METHODS AND ANALYSIS: ExPlas is a double-blinded, randomised controlled clinical single-centre trial. Patients up to 75 years of age with diagnosis early symptomatic phase AD will be recruited from two Norwegian hospitals. ExPlas is plasma drawn by plasmapheresis once a month for 4 months, from a total of 30 fit male donors (aged 18-40, BMI≤27 kg/m2 and maximal oxygen uptake>55 mL/kg/min). All units will be virus inactivated by the Intercept method in accordance with procedures at St. Olavs University Hospital. Comparison with isotonic saline allows differentiation from a non-blood product. The main study consists of 6 rounds of examinations in addition to 12 plasma transfusions divided over three 4-week periods during study year-1. It is also planned to conduct follow-up examinations 2 and 5 years after baseline ETHICS AND DISSEMINATION: Written informed consent will be obtained from all participants and participation is voluntary. All participants have a next of kin who will follow them throughout the study to represent the patient's interest. The study is approved by the Regional Committee for Medical and Health Research Ethics (REK 2018/702) and the Norwegian Medicines Agency (EudraCT No. 2018-000148-24). The study will be published in an open access journal and results will be presented at numerous national and international meetings as well as on social media platforms. TRIAL REGISTRATION NUMBER: EudraCT No. 2018-000148-24. CLINICALTRIALS: gov, NCT05068830.

Perceived and mentally rotated contents are differentially represented in cortical depth of V1.

Primary visual cortex (V1) in humans is known to represent both veridically perceived external input and internally-generated contents underlying imagery and mental rotation. However, it is unknown how the brain keeps these contents separate thus avoiding a mixture of the perceived and the imagined which could lead to potentially detrimental consequences. Inspired by neuroanatomical studies showing that feedforward and feedback connections in V1 terminate in different cortical layers, we hypothesized that this anatomical compartmentalization underlies functional segregation of external and internally-generated visual contents, respectively. We used high-resolution layer-specific fMRI to test this hypothesis in a mental rotation task. We found that rotated contents were predominant at outer cortical depth bins (i.e. superficial and deep). At the same time perceived contents were represented stronger at the middle cortical bin. These results identify how through cortical depth compartmentalization V1 functionally segregates rather than confuses external from internally-generated visual contents. These results indicate that feedforward and feedback manifest in distinct subdivisions of the early visual cortex, thereby reflecting a general strategy for implementing multiple cognitive functions within a single brain region.

Hippocampal and Hippocampal-Subfield Volumes From Early-Onset Major Depression and Bipolar Disorder to Cognitive Decline.

Background: The hippocampus and its subfields (HippSub) are reported to be diminished in patients with Alzheimer's disease (AD), bipolar disorder (BD), and major depressive disorder (MDD). We examined these groups vs healthy controls (HC) to reveal HippSub alterations between diseases. Methods: We segmented 3T-MRI T2-weighted hippocampal images of 67 HC, 58 BD, and MDD patients from the AFFDIS study and 137 patients from the DELCODE study assessing cognitive decline, including subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI), and AD, via Free Surfer 6.0 to compare volumes across groups. Results: Groups differed significantly in several HippSub volumes, particularly between patients with AD and mood disorders. In comparison to HC, significant lower volumes appear in aMCI and AD groups in specific subfields. Smaller volumes in the left presubiculum are detected in aMCI and AD patients, differing from the BD group. A significant linear regression is seen between left hippocampus volume and duration since the first depressive episode. Conclusions: HippSub volume alterations were observed in AD, but not in early-onset MDD and BD, reinforcing the notion of different neural mechanisms in hippocampal degeneration. Moreover, duration since the first depressive episode was a relevant factor explaining the lower left hippocampal volumes present in groups.

"Virus and epidemic": causal knowledge activates prediction error circuitry.

Knowledge about cause and effect relationships (e.g., virus-epidemic) is essential for predicting changes in the environment and for anticipating the consequences of events and one's own actions. Although there is evidence that predictions and learning from prediction errors are instrumental in acquiring causal knowledge, it is unclear whether prediction error circuitry remains involved in the mental representation and evaluation of causal knowledge already stored in semantic memory. In an fMRI study, participants assessed whether pairs of words were causally related (e.g., virus-epidemic) or noncausally associated (e.g., emerald-ring). In a second fMRI study, a task cue prompted the participants to evaluate either the causal or the noncausal associative relationship between pairs of words. Causally related pairs elicited higher activity in OFC, amygdala, striatum, and substantia nigra/ventral tegmental area than noncausally associated pairs. These regions were also more activated by the causal than by the associative task cue. This network overlaps with the mesolimbic and mesocortical dopaminergic network known to code prediction errors, suggesting that prediction error processing might participate in assessments of causality even under conditions when it is not explicitly required to make predictions.

Mandatory processing of irrelevant fearful face features in visual search.

Faces expressing fear may attract attention in an automatic bottom-up fashion. Here we address this issue with magneto-encephalographic (MEG) recordings in subjects performing a demanding visual search combined with the presentation of irrelevant neutral or fearful faces. The impact of the faces' emotional expression on attentional selection was assessed by analyzing the N2pc component--a modulation of the event-related magnetic field response known to reflect attentional focusing in visual search. We observed that lateralized fearful faces elicited an N2pc approximately between 240 and 400 msec in ventral extrastriate cortex that was independent of the N2pc reflecting target selection in visual search. Despite their clear influence on neural processing, fearful faces did not significantly influence behavioral performance. To clarify this discrepancy, we further performed an MEG experiment in which the demands of the search task were reduced. Under those conditions, lateralized fearful faces elicited an N2pc response that was again independent of the N2pc response to the search target. Behavioral performance was, however, influenced in a significant manner, suggesting that for behavioral effects to appear, sufficient attentional resources need to be left unoccupied by the search task--a notion put forward by the perceptual load theory. Our observations are taken to indicate that irrelevant fearful faces influence attentional processing in extrastriate visual cortex in an automatic fashion and independent of other task-relevant attentional operations. However, this may not necessarily be echoed at the behavioral level as long as task-relevant selection operations exhaust attentional resources.

Neuropsychiatric symptoms in at-risk groups for AD dementia and their association with worry and AD biomarkers-results from the DELCODE study.

BACKGROUND: Early identification of individuals at risk of dementia is mandatory to implement prevention strategies and design clinical trials that target early disease stages. Subjective cognitive decline (SCD) and neuropsychiatric symptoms (NPS) have been proposed as potential markers for early manifestation of Alzheimer's disease (AD). We aimed to investigate the frequency of NPS in SCD, in other at-risk groups, in healthy controls (CO), and in AD patients, and to test the association of NPS with AD biomarkers, with a particular focus on cognitively unimpaired participants with or without SCD-related worries. METHODS: We analyzed data of n = 687 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study, including the diagnostic groups SCD (n = 242), mild cognitive impairment (MCI, n = 115), AD (n = 77), CO (n = 209), and first-degree relatives of AD patients (REL, n = 44). The Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale (GDS-15), and Geriatric Anxiety Inventory (GAI-SF) were used to assess NPS. We examined differences of NPS frequency between diagnostic groups. Logistic regression analyses were carried out to further investigate the relationship between NPS and cerebrospinal fluid (CSF) AD biomarkers, focusing on a subsample of cognitively unimpaired participants (SCD, REL, and CO), who were further differentiated based on reported worries. RESULTS: The numbers of reported NPS, depression scores, and anxiety scores were significantly higher in subjects with SCD compared to CO. The quantity of reported NPS in subjects with SCD was lower compared to the MCI and AD group. In cognitively unimpaired subjects with worries, low Aß42 was associated with higher rates of reporting two or more NPS (OR 0.998, 95% CI 0.996-1.000, p < .05). CONCLUSION: These findings give insight into the prevalence of NPS in different diagnostic groups, including SCD and healthy controls. NPS based on informant report seem to be associated with underlying AD pathology in cognitively unimpaired participants who worry about cognitive decline. TRIAL REGISTRATION: German Clinical Trials Register DRKS00007966 . Registered 4 May 2015.

Multimodal MRI analysis of basal forebrain structure and function across the Alzheimer's disease spectrum.

BACKGROUND: Dysfunction of the cholinergic basal forebrain (cBF) is associated with cognitive decline in Alzheimer's disease (AD). Multimodal MRI allows for the investigation of cBF changes in-vivo. In this study we assessed alterations in cBF functional connectivity (FC), mean diffusivity (MD), and volume across the spectrum of AD. We further assessed effects of amyloid pathology on these changes. METHODS: Participants included healthy controls, and subjects with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or AD dementia (ADD) from the multicenter DELCODE study. Resting-state functional MRI (rs-fMRI) and structural MRI data was available for 477 subjects, and a subset of 243 subjects also had DTI data available. Differences between diagnostic groups were investigated using seed-based FC, volumetric, and MD analyses of functionally defined anterior (a-cBF) and posterior (p-cBF) subdivisions of a cytoarchitectonic cBF region-of-interest. In complementary analyses groups were stratified according to amyloid status based on CSF Aß42/40 biomarker data, which was available in a subset of participants. RESULTS: a-cBF and p-cBF subdivisions showed regional FC profiles that were highly consistent with previously reported patterns, but there were only minimal differences between diagnostic groups. Compared to controls, cBF volumes and MD were significantly different in MCI and ADD but not in SCD. The Aß42/40 stratified analyses largely matched these results. CONCLUSIONS: We reproduced subregion-specific FC profiles of the cBF in a clinical sample spanning the AD spectrum. At least in this multicentric cohort study, cBF-FC did not show marked changes along the AD spectrum, and multimodal MRI did not provide more sensitive measures of AD-related cBF changes compared to volumetry.

Methylphenidate does not improve interference control during a working memory task in young patients with attention-deficit hyperactivity disorder.

Patients with attention-deficit/hyperactivity disorder (ADHD) show deficits in working memory (WM) which may be related to prefrontal dysfunction. Methylphenidate (MPH) can restore WM deficits in ADHD by enhancing prefrontal activity. At the same time, changes in striatal activation could cause ADHD patients to be more interference-sensitive during working memory tasks. However, it is unclear whether MPH reduces WM distractibility in ADHD. In this fMRI study, 12 ADHD patients and 12 healthy controls participated on two separate days in a delayed-match-to-sample test. During the delay interval, a distractor stimulus was presented in half of the trials. Children and adolescents with ADHD received MPH only on one of the two sessions. Behavioral data analyses revealed that MPH normalized WM in ADHD. However, MPH did not improve WM performance when a distractor was presented during the delay interval. Functional images showed that MPH enhanced prefrontal activity during the delay in ADHD patients when no distractor was present. If the delay was interrupted by a distractor, only healthy controls showed activation of the caudate. In patients with ADHD, however, in line with behavioral data, MPH did not enhance caudate activity. In healthy youth, caudate activity is involved in interference control allowing the successful maintenance of information in working memory even in the presence of distraction. Our findings suggest that interference control, linked to caudate activity, is not adequately enhanced by MPH in ADHD.