No abstract

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.

BackgroundPRI‐002 is an all‐D‐enantiomeric peptide developed to disassemble Abeta oligomers, which has shown to improve cognition in animal models and which has demonstrated its safety profile in healthy young volunteers (Kutzsche et al. 2020).Method20 AD patients in early disease stages fulfilling the ATN‐criteria were recruited to participate in a single center, randomized, placebo –controlled, double‐blind study. Patients received once daily oral doses of 300 mg PRI‐002 or placebo for 28 days. Safety and efficacy assessments were executed at baseline, day 14, day 28 and day 56 (follow up). Blood sampling was carried out at each time point, EEG and CSF measurements before and at the end of treatment. Imaging (MRI) and functional tests (CERAD, CDR) were performed in parallel to EEG/CSF and additionally at follow up.Result10 patients (age 76.9±3.4, MMSE 28±1.6) received placebo and 9 patients PRI‐002 (72.4±6.9, 27.2±2.9). One patient withdraw informed consent before treatment was started. 13 patients reported in total 27 adverse events while no serious adverse event was noted. There was no statistical difference regarding adverse events between treatment and placebo. EEG and MRI revealed no changes after treatment. While no significant changes were detected in p‐TAU, Abeta1‐42 and Abeta oligomers in CSF before and after treatment, patients receiving PRI‐002 significantly performed better than those receiving placebo in the CERAD word list at follow up (p≤0.05).ConclusionPRI‐002 showed an excellent safety profile in AD patients. While no biomarker changes were detected after 4 weeks of treatment interestingly, an improvement of memory function was noted at follow up. A phase 2 study is scheduled.Kutzsche J, Jürgens D, Willuweit A, Adermann K, Fuchs C, Simons S, Windisch M, Hümpel M, Rossberg W, Wolzt M, Willbold D. Safety and pharmacokinetics of the orally available antiprionic compound PRI‐002: A single and multiple ascending dose phase I study. Alzheimers Dement (N Y). 2020 Mar 20;6(1):e12001. https://doi.org/10.1002/trc2.12001.

No abstract

No abstract

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as informative covariates, vascular risks, brain activity, neuropsychological test etc.,) might provide useful predictions of clinical outcomes during progression towards Alzheimer's disease (AD). The Bayesian approach aims to provide a trade-off by employing relevant features combinations to build decision support systems in clinical settings where uncertainties are relevant. We tested the approach in the MRI data across 959 subjects, aged 59-89 years and 453 subjects with available neuropsychological test scores and CSF biomarker status (amyloid-beta (Aβ)42/40 & and phosphorylated tau (pTau)) from a large sample multi-centric observational cohort (DELCODE). In order to explore the beneficial combinations of information from different sources, we presented a MRI-based predictive modelling of memory performance and CSF biomarker status (positive or negative) in the healthy ageing group as well as subjects at risk of Alzheimer's disease using a Gaussian process multi-kernel framework. Furthermore, we systematically evaluated predictive combinations of input feature sets and their model variations, i.e. (A) combinations of brain tissue classes and feature type (modulated vs. unmodulated), choices of filter size of smoothing (ranging from 0 to 15 mm full width at half maximum), and image resolution (1mm, 2mm, 4mm and 8mm); (B) incorporating demography and covariates (C) the impact of the size of the training data set (i.e., number of subjects); (D) the influence of reducing the dimensions of data and (E) choice of kernel types. Finally, the approach was tested to reveal individual cognitive scores at follow-up (up to 4 years) using the baseline features. The highest accuracy for memory performance prediction was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF-biomarkers explaining 57% of outcome variance in out of sample predictions. The best accuracy for Aβ42/40 status classification was achieved for combination demographics, ApoE4 and memory score while usage of structural MRI improved the classification of individual patient's pTau status.

Background: The mechanisms in the brain that explain the benefits of adherence to the Mediterranean diet (MeDiAd) for cognition are incompletely understood. Here, we investigated whether fractional anisotropy (FA) in hippocampus-relevant white-matter tracts mediates the association between baseline MeDiAd and verbal episodic memory over four years. Methods: Participants with baseline diffusion-weighted imaging data from the DELCODE cohort study were selected, including healthy older adults with and without subjective cognitive decline and patients with mild cognitive impairment (n = 376; age: 71.47 plus-or-minus sign 6.09 years; 48.7% female). Demographic, MeDiAd, and diffusion data were obtained at baseline. Verbal episodic memory was assessed at baseline and four yearly follow-ups. The association between baseline MeDiAd and verbal episodic memory's mean and rate of change over four years and the mediation of that association by baseline white-matter tracts were tested with latent growth curve modeling. Potential mediators were selected based on the association with hippocampal volume. Results: Baseline MeDiAd was associated with verbal episodic memory four years later (latent intercept; 95% confidence interval, CI [0.01, 0.32]) but not with its rate of change (latent slope) over this period. Only baseline Fornix FA, among four potential mediators (the cingulum ventral, corticospinal tract, and superior longitudinal fasciculus II), mediated this association (latent intercept; 95% CI [0.002, 0.09]). Conclusions: Higher Fornix FA explains the association between higher baseline MeDiAd and better memory four years later in pre-dementia stages. Fornix FA may be a useful response biomarker of Mediterranean diet interventions on memory.

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer`s disease (AD). Brain macrophage populations differentially modulate the immune response to AD pathology according to the disease stage. Triggering receptor expressed on myeloid cells 2 (TREM2) is known to play a protective role in AD and has been postulated as a putative therapeutic target. Whether, and to which extent TREM2 expression can be modulated in the aged macrophage population of the brain is unknown, emphasizing the need for a human, patient-specific model. Using cells from AD patients and matched controls (CO) we designed an assay based on monocyte-derived macrophages to mimic brain-infiltrating macrophages and to assess the individualized TREM2 synthesis in vitro. We systematically assessed the effects of short-term (acute—2 days) and long-term (chronic—10 days) M1- (LPS), M2- (IL-10, IL-4, TGF-β), and M0- (vehicle) macrophage differentiation on TREM2 synthesis. Moreover, the effects of retinoic acid (RA), a putative TREM2 modulator, on individualized TREM2 synthesis were assessed. We report increased TREM2 synthesis after acute M2- compared to M1-differentiation in CO- but not AD-derived cells. Chronic M2- and M0-differentiation however resulted in an increase of TREM2 synthesis in both AD- and CO-derived cells while chronic M1-differentiation increased TREM2 in AD-derived cells only. Moreover, chronic M2- and M0-differentiation improved the amyloid-β (Aβ) uptake of the CO-derived whereas M1-differentiation of the AD-derived cells. Interestingly, RA-treatment did not modulate TREM2. In the age of personalized medicine, our individualized model could be used to screen for potential drug-mediated treatment responses in vitro. Graphical Abstract Triggering receptor expressed on myeloid cells 2 (TREM2) has been postulated as a putative therapeutic target in Alzheimer’s disease (AD). Using cells from AD patients and matched controls (CO), we designed a monocyte-derived macrophages (Mo-MФs) assay to assess the individualized TREM2 synthesis in vitro. We report increased TREM2 synthesis after acute M2- compared to M1- macrophage differentiation in CO- but not AD-derived cells. Chronic M2- and M0- differentiation however resulted in an increase of TREM2 synthesis in both AD- and CO-derived cells while chronic M1-differentiation increased TREM2 in AD-cells only