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Introduction: We investigated amyloid‐burden quantification in a mixed memory clinic population. Methods: [18F]Florbetaben amyloid‐PET (positron emission tomography) scans of 348 patients were visually read and quantified using the Centiloid (CL) method. General linear models were used to assess CL differences across syndromic and etiological diagnosis. Linear mixed models were fitted to assess the predictive value of visual read (VR) and CL on longitudinal Mini‐Mental Status Examination (MMSE). Results: CL was associated with syndromic (F = 4.42, p = 0.014) and etiological diagnosis (F = ‐12.66, p < 0.001), with Alzheimer's disease (AD) patients showing the highest amyloid burden (62.9 ± 27.5), followed by dementia with Lewy bodies (DLB) (25.3 ± 35.5) and cardiovascular disease (CVD) (16.7 ± 24.5), and finally frontotemporal lobe degeneration (FTLD) (5.0 ± 17.22, t = –12.66, p < 0.001). CL remained predictive of etiological diagnosis (t = –2.41, p = 0.017) within the VR+ population (N = 157). VR was not a significant predictor of MMSE (t = –1.53, p = 0.13) for the SCD population (N = 90), whereas CL was (t = ‐3.30, p = 0.001). Discussion: The extent of amyloid pathology through quantification holds clinical value, potentially in the context of differential diagnosis as well as prognosis. [ABSTRACT FROM AUTHOR]

Introduction: We aim to study the effect of a more precise diagnosis, by means of amyloid positron emission tomography (PET), on institutionalization, mortality, and health‐care costs. Methods: Between October 27, 2014 and December 31, 2016, we offered amyloid PET to all patients as part of their diagnostic work‐up. Patients who accepted to undergo amyloid PET (n = 449) were propensity score matched with patients without amyloid PET (n = 571, i.e., no PET). Matched groups (both n = 444) were compared on rate of institutionalization, mortality, and health‐care costs in the years after diagnosis. Results: Amyloid PET patients had a lower risk of institutionalization (10% [n = 45] vs. 21% [n = 92]; hazard ratio [HR] = 0.48 [0.33–0.70]) and mortality rate (11% [n = 49] vs. 18% [n = 81]; HR = 0.51 [0.36–0.73]) and lower health‐care costs in the years after diagnosis compared to matched no‐PET patients (β = −4573.49 [−6524.76 to −2523.74], P‐value < 0.001). Discussion: A more precise diagnosis in tertiary memory clinic patients positively influenced the endpoints of institutionalization, death, and health‐care costs. [ABSTRACT FROM AUTHOR]

Background: In recent years, the availability of biofluid markers in Alzheimer's disease (AD) has increased substantially, but it is unclear to what extend these are applied to support drug development. Therefore, we provide an overview of biofluid biomarker use within trials. Method: To identify how fluid biomarkers are used in clinical trials, we performed a search (8‐FEB‐2022) on www.clinicaltrials.gov, using the search term 'Alzheimer's disease', and selected trials aimed at disease modification starting from 1‐JAN‐2017 to 1‐JAN‐2022. Biofluid markers and their purpose in each trial were described. Results are summarized by trial phase, target class, and endpoint information. Result: We identified 186 trials of which 44% used biofluid markers. 15% of phase 1 trials, 15% of phase 2 trials, and 6% of phase 3 and 4 trials employ fluid biomarkers as primary outcome (Figure 1). Blood and CSF biomarkers were used equally frequent. CSF biomarkers for Aβ, Tau, and other biomarkers were employed in 21%, 25%, and 16% of the 186 trials, respectively. Blood biomarkers for Aβ, Tau, and other biomarkers were used in 14%, 13%, and 23% of the trials, respectively. Moving further in the drug development phases, contribution of classic AD biomarkers increased, especially in CSF. Overall, a combination of Aβ, Tau and other biomarkers was used most frequent. 25% of the trials use biofluid target engagement markers. Target engagement marker use is most prominent in amyloid and tau targeting drugs. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis, gut‐brain axis targeting drugs. Conclusion: There exists a need for new fluid biomarkers, to reflect pathology which can be used in certain target classes where there currently is a lack of fluid biomarkers. To support future use biofluid markers as surrogate outcomes, research into the specific pathological processes they reflect and their correlation with cognition is warranted. This can pave the way into implementation of surrogacy biomarkers in AD clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to assess the usefulness of the appropriate use criteria (AUC) for amyloid imaging in an unselected cohort. Methods: We calculated sensitivity and specificity of appropriate use (increased confidence and management change), as defined by Amyloid Imaging Taskforce in the AUC, and other clinical utility outcomes. Furthermore, we compared differences in post–positron emission tomography diagnosis and management change between "AUC‐consistent" and "AUC‐inconsistent" patients. Results: Almost half (250/507) of patients were AUC‐consistent. In both AUC‐consistent and AUC‐inconsistent patients, post–positron emission tomography diagnosis (28%–21%) and management (32%–17%) change was substantial. The Amyloid Imaging Taskforce's definition of appropriate use occurred in 55/507 (13%) patients, detected by the AUC with a sensitivity of 93%, and a specificity of 56%. Diagnostic changes occurred independently of AUC status (sensitivity: 57%, specificity: 53%). Discussion: The current AUC are not sufficiently able to discriminate between patients who will benefit from amyloid positron emission tomography and those who will not. [ABSTRACT FROM AUTHOR]

Introduction Loss of synapses best correlates to cognitive deficits in Alzheimer's disease (AD) in which oligomeric neurotoxic species of amyloid-β appears to contribute synaptic pathology. Although a number of clinical pathologic studies have been performed with limited sample size, there are no systematic studies encompassing large samples. Therefore, we performed a meta-analysis study. Methods We identified 417 publications reporting postmortem synapse and synaptic marker loss from AD patients. Two meta-analyses were performed using a single database of subselected publications and calculating the standard mean differences. Results Meta-analysis confirmed synaptic loss in selected brain regions is an early event in AD pathogenesis. The second meta-analysis of 57 synaptic markers revealed that presynaptic makers were affected more than postsynaptic markers. Discussion The present meta-analysis study showed a consistent synaptic loss across brain regions and that molecular machinery including endosomal pathways, vesicular assembly mechanisms, glutamate receptors, and axonal transport are often affected. [ABSTRACT FROM AUTHOR]

Background: Age‐related cognitive decline (ARCD) refers to the cognitive changes that can occur in individuals as a consequence of aging, distinct from cognitive changes due to a primary neurodegenerative process (e.g., Alzheimer's Disease), cerebral ischemia (e.g., vascular dementia), or other pathology. However, there is sparse research into direct interventions for ARCD. Recent research suggests that the underlying mechanism behind ARCD is a loss of synaptic plasticity, which is essential for learning, memory, and the formation of memory engrams, in part through its effects on dendritic spine morphology. Therefore, therapies aimed at rescuing dendritic spine density and increasing synaptic plasticity may be viable strategies for decreasing the effects of ARCD. Souvenaid contains Fortasyn Connect, a specific combination of nutrients designed to enhance synapse formation by providing precursors and cofactors for phospholipid synthesis. In prodromal Alzheimer's disease, Fortasyn Connect showed beneficial effects on memory, cognition, and brain atrophy [1]. In addition, the data from this study suggest a stronger effect would be expected in participants at earlier stages of prodromal AD. Souvenaid has not yet been tested in individuals with ARCD. Method: Towards this end, we present the design of a 6‐month single‐center pilot clinical trial that aims to perform all assessments via a telemedicine platform. The study design specifically factors in local COVID‐19 restrictions. We plan to recruit 60 participants aged 55‐89 with age‐related cognitive decline, who will be screened and randomized to the oral multi‐nutrient combination (Souvenaid) or placebo on a 1:1 basis. The main outcome of this trial is feasibility (recruitment rate and time, adherence rate and retention rate). Other outcomes include memory (e.g. Ray Verbal Learning Task), cognition (e.g. Oral Trail Making Test), and quality of life (e.g. Amsterdam IADL Questionnaire) outcome measures. Result: Results of REACTION will provide insight into the feasibility of a virtual study with Souvenaid in ARCD. Conclusion: With the rapidly growing prevalence of ARCD and no pharmacological interventions currently available, nutritional interventions may potentially play an important role to reduce or delay the effects of ARCD. [ABSTRACT FROM AUTHOR]

A new Begonia species from Laos and Thailand is described. It belongs to Begonia sect. Tetraphila, along with 30 other species which are all endemic to Africa. This is the first record of any of the 65 currently accepted sections in Begonia transgressing continental borders. A dated molecular phylogeny places the split of the new Asian species from its African congeners during the late Miocene to the early Pleistocene. As the species is a hygromesophilous epiphyte limited to tropical forest, no suitable corridor for migration existed during that time and the cause of the Afro-Asian disjunction probably is a long-distance dispersal event. The discovery of B. afromigrata emphasises the importance of chance in the assembly of tropical floras. [ABSTRACT FROM AUTHOR]

Implant companies have been promoting two-piece implants with microtextured collars in the interest of hard tissue preservation and/or soft tissue integration. However, this rationale may not be justified. Based on comparative studies currently available, it is unclear whether microroughened implant necks reduce crestal bone loss. A possible effect may be overruled by the establishment of a biologic width or by other factors influencing crestal bone remodeling. In addition, the orientation and attachment of the collagen fibers in the peri-implant mucosa are a little different because the surface roughness varies at the level of the implant neck. The clinician should be cautious when using these modified implants because the impact of microtextured collars on the initiation and progression of peri-implant pathology is currently unknown. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) coincides with a progressive decline in instrumental activities of daily living (iADL), such as cooking and everyday technology. Souvenaid is a medical food designed to enhance synapse formation and function; it contains the specific nutrient combination Fortasyn Connect. Randomized controlled trials showed beneficial effects on memory in mild AD patients and on the cognitive‐functional outcome CDR‐SB and hippocampal atrophy in prodromal AD. In this observational study we evaluated the effects of Souvenaid on iADL of people with mild AD in real‐world, daily clinical practice. Method: Participants were recruited from specialized memory clinics and received the medical food once a day. iADL were assessed at baseline, 6 months follow‐up, and optionally at 12 months follow‐up, using the Amsterdam iADL questionnaire (A‐IADL). Changes in A‐IADL scores were compared with a reference population (n=57), using a one‐sample t‐test. Exploratory sub‐group analyses will also be presented. Result: 116 participants were enrolled in the study. Self‐reported adherence to Souvenaid was high. The 6‐month change from baseline in A‐IADL was significantly less than the dementia reference population (‐1.56 [SD 6.71] vs. ‐3.68 respectively, p=0.009). The effect was maintained in participants completing the 12‐month period with a mean change from baseline of ‐3.12 (SD 8.04) compared with the reference value of ‐7.35 (p=0.011). People using AD medication showed a mean 6‐month change from baseline of ‐1.29 [SD 5.38]. People not using AD medication showed a mean change of ‐1.65 [SD 7.14]. Participants completing the 12‐month period showed a mean change of ‐5.62 [SD 6.19] when using AD medication and ‐2.06 [SD 8.63] when not using AD medication. In individuals with baseline MMSE > median, 6‐month change from baseline was ‐1.34 [SD 5.76] and ‐1.99 [SD 7.86] in individuals when baseline MMSE < median, whereas the 12‐month changes from baseline were ‐4.24 [SD 7.32] and – 1.91 [SD 8.89], respectively. Conclusion: People with mild AD receiving Souvenaid showed less decline in iADL over 6 and 12 months compared with a reference population. This observational study suggests that this specific medical food might have an impact on iADL in mild AD in a real‐world clinical setting. [ABSTRACT FROM AUTHOR]

Background: Even though there is no curative treatment for Alzheimer’s disease (AD) yet, an accurate diagnosis is essential, as it is a starting point to arrange proper care, which in turn may lead to beneficial health outcomes. Amyloid‐PET contributes to an accurate diagnosis and we hypothesize that this predisposes toward a more benign disease trajectory in terms of rate of institutionalization and mortality. Method: We included consecutive patients who had their baseline visit at the Alzheimer center Amsterdam between 2015 and 2016. During this period, we offered amyloid‐PET to all participants. Patient underwent amyloid‐PET as part of their diagnostic work‐up and were propensity score matched with patients without amyloid‐PET (i.e. no‐PET). Propensity score matching was performed with nearest neighbor 1‐to‐1 matching without replacement and based on baseline characteristics, resulting in two matched groups of n=444 patients each. The endpoints of the study were admission to a nursing home and mortality retrieved from statistics Netherlands. Result: Patients (matched cohort) had a mean age of 64±8, 40% (n=353) female, MMSE 25±4 and 43% (n=379) had dementia at baseline. Mean follow‐up duration was 3±1 for institutionalization and 4±1 for mortality. In the amyloid‐PET group, 10% (n=45) of patients were admitted to a nursing home, compared to 21% (n=92) of no‐PET patients. The amyloid‐PET group (HR=0.48 [0.33‐0.70]) had a lower risk of institutionalization compared to no‐PET patients, corresponding to a 1.5 year delay in institutionalization. Moreover, patients with amyloid‐PET had a lower mortality rate compared to matched no‐PET patients (11% (n=49) vs 18% (n=81); HR=0.51 [0.36‐0.73]), which corresponds with a 1.4 year longer survival. We found no differences between amyloid‐positive and amyloid negative patients). Conclusion: We demonstrated that a more accurate diagnosis, operationalized by means of adding amyloid‐PET to the diagnostic work‐up, positively influenced time to institutionalization and death in memory clinic patients, independent of syndrome diagnosis. This provides evidence for the notion that a well‐informed patient has better health outcomes. [ABSTRACT FROM AUTHOR]

The accumulation of five murine single-chain variable fragments, binding to dihydroflavonol 4-reductase, was analyzed in transgenic Petunia hybrida plants. The five scFv-encoding sequences were cloned in an optimized plant transformation vector for expression in the cytosol under control of the 35S promoter. In a transient expression assay we found that the scFv expression levels were reproducible and correlated with those in stably transformed petunia. Our results show that accumulation in the cytosol strongly depends on the intrinsic properties of the scFv fragment. Three of the five scFv fragments accumulated to unexpectedly high levels in the cytosol of the primary transformants, but no phenotypic effect could be detected. Experimental results indicate that one of the scFv fragments accumulated in the cytosol to 1% of the total soluble protein as a functional antigen-binding protein in the absence of disulphide bonds. This observation supports the idea that certain antibody fragments do not need disulphide bonds to be stable and functional. Such scFv scaffolds provide new opportunities to design scFv fragments for immunomodulation in the cytosol.