Distinct transthyretin oxidation isoform profile in spinal fluid from patients with Alzheimer’s disease and mild cognitive impairment

BACKGROUND: Transthyretin (TTR), an abundant protein in cerebrospinal fluid (CSF), contains a free, oxidation-prone cysteine residue that gives rise to TTR isoforms. These isoforms may reflect conditions in vivo. Since increased oxidative stress has been linked to neurodegenerative disorders such as Alzheimer’s disease (AD) it is of interest to characterize CSF-TTR isoform distribution in AD patients and controls. Here, TTR isoforms are profiled directly from CSF by an optimized immunoaffinity-mass spectrometry method in 76 samples from patients with AD (n = 37), mild cognitive impairment (MCI, n = 17)), and normal pressure hydrocephalus (NPH, n = 15), as well as healthy controls (HC, n = 7). Fractions of three specific oxidative modifications (S-cysteinylation, S-cysteinylglycinylation, and S-glutathionylation) were quantitated relative to the total TTR protein. Results were correlated with diagnostic information and with levels of CSF AD biomarkers tau, phosphorylated tau, and amyloid β(1-42) peptide. RESULTS: Preliminary data highlighted the high risk of artifactual TTR modification due to ex vivo oxidation and thus the samples for this study were all collected using strict and uniform guidelines. The results show that TTR is significantly more modified on Cys(10) in the AD and MCI groups than in controls (NPH and HC) (p ≤ 0.0012). Furthermore, the NPH group, while having normal TTR isoform distribution, had significantly decreased amyloid β peptide but normal tau values. No obvious correlations between levels of routine CSF biomarkers for AD and the degree of TTR modification were found. CONCLUSIONS: AD and MCI patients display a significantly higher fraction of oxidatively modified TTR in CSF than the control groups of NPH patients and HC. Quantitation of CSF-TTR isoforms thus may provide diagnostic information in patients with dementia symptoms but this should be explored in larger studies including prospective studies of MCI patients. The development of methods for simple, robust, and reproducible inhibition of in vitro oxidation during CSF sampling and sample handling is highly warranted. In addition to the diagnostic information the possibility of using TTR as a CSF oxymeter is of potential value in studies monitoring disease activity and developing new drugs for neurodegenerative diseases

Brain serotonin 4 receptor binding is inversely associated with verbal memory recall

BACKGROUND: We have previously identified an inverse relationship between cerebral serotonin 4 receptor (5‐HT (4)R) binding and nonaffective episodic memory in healthy individuals. Here, we investigate in a novel sample if the association is related to affective components of memory, by examining the association between cerebral 5‐HT (4)R binding and affective verbal memory recall. METHODS: Twenty‐four healthy volunteers were scanned with the 5‐HT (4)R radioligand [(11)C]SB207145 and positron emission tomography, and were tested with the Verbal Affective Memory Test‐24. The association between 5‐HT (4)R binding and affective verbal memory was evaluated using a linear latent variable structural equation model. RESULTS: We observed a significant inverse association across all regions between 5‐HT (4)R binding and affective verbal memory performances for positive (p = 5.5 × 10(−4)) and neutral (p = .004) word recall, and an inverse but nonsignificant association for negative (p = .07) word recall. Differences in the associations with 5‐HT (4)R binding between word categories (i.e., positive, negative, and neutral) did not reach statistical significance. CONCLUSION: Our findings replicate our previous observation of a negative association between 5‐HT (4)R binding and memory performance in an independent cohort and provide novel evidence linking 5‐HT (4)R binding, as a biomarker for synaptic 5‐HT levels, to the mnestic processing of positive and neutral word stimuli in healthy humans

Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer's Disease:A Randomized Controlled Trial

Background: Studies of physical exercise in patients with Alzheimer’s disease (AD) are few and results have been inconsistent. Objective: To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD. Methods: In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was changed from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms. Results: The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: –3.5, 95% confidence interval (CI) –5.8 to –1.3, p = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p = 0.028), suggesting a dose-response relationship between exercise and cognition. Conclusions: This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity.</jats:p

Neuropsychology/computerized neuropsychological assessment

AbstractBackgroundDifferential diagnostics in dementia is challenging. To date, the basic assessment still includes imaging of the brain and cognitive testing with pen and paper. Web‐based cognitive tests however hold potential for standardized and low‐cost screening in clinical workup. How they perform when combined with imaging of the brain is unknown. We therefore evaluated the accuracy of a new web‐based cognitive battery (Muistikko [1]) detecting different types of dementia, when combined with brain MRI, and compared this to traditional cognitive testing and MRI.MethodWe included 229 subjects from two memory clinic cohorts (PredictND and VPH‐DARE), consisting of 188 controls, 29 patients with Alzheimer's dementia (AD), 7 with frontotemporal dementia (FTD) and 5 with vascular dementia (VaD) (Table 1). All patients performed a traditional cognitive test battery (consisting of MMSE, RAVLT, TMT‐A and B, Animal Fluency), web‐based cognitive testing and had MRI of the brain. Although Muistikko is composed of seven subtasks, only global cognitive score (GCS) was used as defined in [1]. From MRI, multiple imaging biomarkers were defined [2]. Disease‐state index classifier was developed from the predictors [2]. Cross‐validation was used to calculate balanced accuracy (BACC; average of sensitivities for each diagnostic group). Given the class imbalance, we also calculated prevalence corrected accuracy (PACC).ResultBACC was 66 % and PACC 64% when using the traditional cognitive test battery + MRI. Both BACC and PAC were 69 % when using the web‐based cognitive testing + MRI (Table 2). Of note, since we compare four diagnostic groups, BACC by guessing would be 25%.ConclusionThis study shows that combining web‐based cognitive tests with MRI data results in high accuracy when separating different types of dementia. The results were comparable with the standard traditional work‐up. Web‐based cognitive testing is therefore a promising tool to support the clinician in the daily challenge of differential diagnostics, especially when combined with MRI data. References: [1] Paajanen, S. et al. Detecting cognitive disorders using Muistikko web‐based cognitive test battery. Alzheimer's & Dementia 13(7):Supplement,P234‐P235,2017 [2] Bruun, M. et al. Evaluating combinations of diagnostic tests to discriminate different dementia types. Alzheimers Dement 2018 Aug17;10:509‐51

The Center for Integrated Molecular Brain Imaging (Cimbi) database

AbstractWe here describe a multimodality neuroimaging containing data from healthy volunteers and patients, acquired within the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi) in Copenhagen, Denmark. The data is of particular relevance for neurobiological research questions related to the serotonergic transmitter system with its normative data on the serotonergic subtype receptors 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 and the 5-HT transporter (5-HTT), but can easily serve other purposes.The Cimbi database and Cimbi biobank were formally established in 2008 with the purpose to store the wealth of Cimbi-acquired data in a highly structured and standardized manner in accordance with the regulations issued by the Danish Data Protection Agency as well as to provide a quality-controlled resource for future hypothesis-generating and hypothesis-driven studies.The Cimbi database currently comprises a total of 1100 PET and 1000 structural and functional MRI scans and it holds a multitude of additional data, such as genetic and biochemical data, and scores from 17 self-reported questionnaires and from 11 neuropsychological paper/computer tests. The database associated Cimbi biobank currently contains blood and in some instances saliva samples from about 500 healthy volunteers and 300 patients with e.g., major depression, dementia, substance abuse, obesity, and impulsive aggression. Data continue to be added to the Cimbi database and biobank

SARS-CoV-2 antibody prevalence among homeless people and shelter workers in Denmark:a nationwide cross-sectional study

BACKGROUND: People experiencing homelessness (PEH) and associated shelter workers may be at higher risk of infection with “Severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2). The aim of this study was to determine the prevalence of SARS-CoV-2 among PEH and shelter workers in Denmark. DESIGN AND METHODS: In November 2020, we conducted a nationwide cross-sectional seroprevalence study among PEH and shelter workers at 21 recruitment sites in Denmark. The assessment included a point-of-care test for antibodies against SARS-CoV-2, followed by a questionnaire. The seroprevalence was compared to that of geographically matched blood donors considered as a proxy for the background population, tested using a total Ig ELISA assay. RESULTS: We included 827 participants in the study, of whom 819 provided their SARS-CoV-2 antibody results. Of those, 628 were PEH (median age 50.8 (IQR 40.9–59.1) years, 35.5% female) and 191 were shelter workers (median age 46.6 (IQR 36.1–55.0) years and 74.5% female). The overall seroprevalence was 6.7% and was similar among PEH and shelter workers (6.8% vs 6.3%, p = 0.87); and 12.2% among all participants who engaged in sex work. The overall participant seroprevalence was significantly higher than that of the background population (2.9%, p < 0.001). When combining all participants who reported sex work or were recruited at designated safe havens, we found a significantly increased risk of seropositivity compared to other participants (OR 2.23, 95%CI 1.06–4.43, p = 0.02). Seropositive and seronegative participants reported a similar presence of at least one SARS-CoV-2 associated symptom (49% and 54%, respectively). INTERPRETATIONS: The prevalence of SARS-CoV-2 antibodies was more than twice as high among PEH and associated shelter workers, compared to the background population. These results could be taken into consideration when deciding in which phase PEH are eligible for a vaccine, as part of the Danish national SARS-CoV-2 vaccination program rollout. FUNDING: TrygFonden and HelseFonden. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-022-13642-7