bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurement bias in depression assessment according to brain amyloid burden, cognitive function, and sex in the A4 study
Authors: Thompson Louisa I. , Jones Richard N.
Published: December 2020

Background

We sought to identify measurement bias (differential item functioning, DIF) in the Geriatric Depression Scale (15 item version) attributable to cerebral amyloid level (Aβ) among cognitively normal older adults. Specifically, we were interested in determining if endorsement of self‐reported memory problems on the GDS‐15 differed by Aβ level. We hypothesized that persons with high Aβ would have a greater probability of endorsing memory problems than those with low Aβ, consistent with the literature showing that subjective cognitive decline in older adults is associated with increased AD risk. We also examined DIF attributable to level of cognitive functioning and sex as positive controls that may account for differences in self‐reported depression.

Method

Analyses were conducted using the pre‐randomization database of the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4)/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study (N=3,961). We used the MIMIC (multiple indicators, multiple causes) approach to detect DIF. The MIMIC approach is consistent with item response theory, and allows for the detection of uniform DIF for predictors that are either discretely observed (sex) or continuously observed (Aβ level, cognitive function).

Result

We found DIF with respect to Aβ level, sex, and cognitive functioning. Most DIF detected was of a trivial effect size with some showing small‐to‐moderate effect sizes. Mild DIF, attributable to Aβ level, was shown for the GDS memory item in the hypothesized direction: after adjustment for depressive symptom severity (overall GDS symptoms), persons with high Aβ had a greater probability of endorsing memory problems than those with low Aβ (effect size = 0.22, p <.001). Interestingly, DIF for 2 items assessing hopelessness were also observed according to high Aβ versus low Aβ. Despite these findings we determined that there was negligible impact of DIF attributable to Aβ level on overall depressive symptom level.

Conclusion

Participant responses on items of the GDS‐15 are sensitive to Aβ burden, sex, and level of cognitive functioning over and above what would be expected given the effect of those factors on depressive symptom severity overall. However, these direct effects are of small magnitude and do not appreciably impact the validity of inferences based on the GDS‐15.
In vivo assessment of the noradrenergic nucleus locus coeruleus in Alzheimer’s disease and other types of dementia
Authors: Giorgi Filippo Sean , Galgani Alessandro , Lombardo Francesco , Palermo Giovanni , Hana Hlavata , Daniele Della Latta , Ghicopulos Irene , Martini Nicola , Baldacci Filippo , Coi Alessio , Tognoni Gloria , Siciliano Gabriele , Ceravolo Roberto , Pavese Nicola , Fornai Francesco , Bonuccelli Ubaldo
Published: December 2020

Background

The Locus Coeruleus (LC) is the main noradrenergic nucleus of the brain. Pathological analysis in humans have shown that LC is degenerated in Alzheimer’s disease (AD), and that its impairment might start years before the occurrence of cognitive impairment. Several experimental studies in animal models even suggested a pathogenetic role of an early LC degeneration in AD pathogenesis. LC neuromelanin‐containing neurons can be assessed by using MRI scan, in T1‐weighted sequences. In this study, we assessed in vivo the integrity of LC by 3T MRI in patients with dementia due to AD (ADD) and in MCI subjects, comparing them with patients with Fronto‐temporal dementia (FTD), with patients with Lewy Body Dementia (LBD)/ Parkinson’s Disease Dementia (PDD) and with healthy controls (HC).

Method

234 subjects (HC=60; MCI=80; ADD=40; FTD=18; LBD/PDD=36) were submitted to a 3 Tesla brain MRI (Signa‐GEH), including neuromelanin (NM)‐sensitive FSE T1‐weighted sequences for LC study. The sequences were then evaluated using a semi‐automatic software by blinded operators. An indirect measures of LC volume, based on the number of Voxels selected, is expressed by the parameter VOX. All subjects underwent detailed clinical and neuropsychological assessment.

Result

VOX was significantly lower in ADD compared to HC, while no differences were observed between HC and FTD. The lowest values of were observed in LBD/PDD and Early Onset AD (EOAD) patients. MCI subjects showed an LC signal lower than HC, although not statistically significant. Patients with confirmed AD pathology presented lower values of VOX than HC, and their cognitive performances correlated with the degree of LC signal reduction.

Conclusion

We observed in vivo a marked alteration of LC signal in AD patients, compared to healthy controls, in line with the hypothesis of LC involvement in AD pathogenesis; the severe alteration found in EOAD, further supports this association. As expected from neuropathological and NM‐MRI studies, also PDD/LBD showed LC alterations, while FTD did not. In MCI a trend was observed, even if not significant: a longitudinal study is required to evaluate potential association with ADD conversion rate. Funding sponsor: Ministero della Salute PE‐2013‐02359574 (P.I.: FSG).
Increased connectivity in several bilateral frontal and fronto‐parietal networks predicts depressive symptoms in mid‐ to late‐life diabetics
Authors: Salardini Arash , Shen Xilin , Hashemi‐Aghdam Arsalan , Laltoo Emily , Savoia Sarah , Tokoglu Fuyuze , Constable Todd
Published: December 2020

Background

Depressive symptoms may be a feature of vascular cognitive impairment secondary to diabetes. There is significant biotypic diversity amongst individuals with depressive symptoms depending on the causes and symptoms. In this study we determined the brain networks which are best correlated with depressive traits in our cohort of diabetic individuals.

Method

49 diabetic patients were recruited and underwent comprehensive neuropsychological testing as well as MRI imaging including structural MRI and rs‐fMRI. A linear regression model was built on a general functional connectivity matrix, derived from the rs‐fMRI data, to predict depression symptoms as measured by Beck’s Depression Inventory (BDI). The leave‐one‐out cross validation method was used to test the model.

Results

CPM was applied to imaging from 49 individuals aged 55‐90 (Mean 69, SD 8) with a diagnosis of diabetes (Mean HbA1c = 6.88, SD 1) with Fazekas scores of 0‐3 (mean 1.04, SD 0.78). BDI scores ranged 0‐20 (mean 6.12, SD 4.63) while MOCA scores spanned 13‐30 (mean 25.14, SD 3.51). A positive predictive model was discovered (R2 =0.3514, p=0.0143) which contained increased connectivity in several frontal and frontoparietal networks. Specifically, stronger connections between bilateral ventromedial prefrontal cortices and dorsal prefrontal cortices (L > R) appeared to predict higher BDI scores. No statistically significant negative predictive model (where weaker connections predicted higher BDI scores) were found.

Conclusion

In this study we use connectome‐based predictive modelling (CPM) to find connections which may predict the presence of depressive symptoms in diabetic individuals. Unlike most connectome‐based techniques which determine connections which have an association with behavioral measures, CPM finds networks which likely predict behavioral scores. Our findings are consistent with what we know about the neural correlates of depression but represent the first hypothesis‐free connectivity study of depressive symptoms in mid to late‐life diabetes.
Mean arterial pressure during cerebral perfusion MRI: An arterial spin‐labeling study in younger and older adults
Authors: Sible Isabel J. , Yew Belinda , Dutt Shubir , Li Yanrong , Ho Jean K. , Jang Jung Yun , Blanken Anna E. , Gaubert Aimee , Marshall Anisa J. , Kapoor Arunima , Shao Xingfeng , Wang Danny J.J. , Nation Daniel A.
Published: December 2020

Background

High blood pressure (BP) and low cerebral blood flow (CBF) have been independently related to Alzheimer’s disease (AD) pathophysiology. Increased cerebrovascular resistance index (CVRi), the ratio of mean arterial pressure (MAP) to CBF, has also been linked to AD risk in older adults. Autoregulatory mechanisms maintain steady perfusion across a range of MAP values through changes in cerebrovascular resistance in healthy individuals. Age‐dependent cerebrovascular stiffening can disrupt cerebrovascular resistance, leaving the brain vulnerable to hypoperfusion with increased MAP. No studies have evaluated MAP during perfusion MRI to further evaluate whether high BP may be related to lower CBF, and whether this relationship is age‐dependent. We studied MAP during perfusion MRI in a sample of younger and older adults using an MRI‐compatible device to continuously monitor MAP.

Method

Community‐dwelling older adults (n=21; age 56‐87) free of dementia or stroke, and healthy younger adults (n=16; age 18‐34) underwent resting pseudo‐continuous arterial spin‐labelling (pCASL)‐MRI to quantify CBF during simultaneous in‐scanner, continuous MAP monitoring. Average MAP and CBF were calculated over the 5 minute scan. Multiple linear regression examined the relationship between MAP and CBF for younger and older adults, controlling for age and sex.

Result

Older adults with higher MAP during perfusion MRI exhibited significantly lower CBF levels (R2
= .49, β = ‐.23, p = .02). MAP showed no significant relationship with CBF in younger adults.

Conclusion

This is the first study to evaluate MAP during perfusion MRI. Findings indicate that higher MAP is correlated with lower CBF in real time in older adults only. We hypothesize that higher MAP may cause decreased CBF through chronic increases in cerebrovascular resistance. Our approach utilizes pCASL‐MRI, capturing CBF to capillaries and smaller arterioles that are susceptible to age‐related microvascular injury. It remains unclear whether the relationship between MAP and microvascular perfusion plays a role in the increased dementia risk associated with high CVRi, but increased CVRi and decreased CBF are associated with dementia. Future work will explore the role of BP during perfusion MRI and whether it may contribute to diagnosis, prognosis or treatment decision‐making to help prevent dementia.
The effect of vitamins on cognitive function in middle‐aged and older adults without dementia
Authors: Suh Seung Wan , Kim Hye Sung , Han Ji Hyun , Bae Jong Bin , Oh Dae Jong , Han Ji Won , Kim Ki Woong
Published: December 2020

Background

Evidence suggests that vitamins might have a beneficial effect for cognition. The current systematic review aims to investigate the effect of B vitamins, antioxidant vitamins, and vitamin D on cognitive function in the non‐demented middle‐aged or older people.

Method

Randomized, or quasi‐randomized clinical trials comparing vitamin supplementation with a control group were included in the standard inverse‐variance random‐effects meta‐analyses. We searched PubMed/MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane Library databases for articles until November 2019, and used Risk of Bias tool to evaluate methodological quality of them.

Result

A total of twenty‐three studies for B vitamins (n = 22 – 1,053), five studies for antioxidant vitamins (n = 185 – 5,226), and six studies for vitamin D (n = 55 – 4,122) were included in the meta‐analyses. We found that B vitamins had a beneficial effect on global cognitive function (Standardized mean difference [SMD] ‐0.23, 95% CI ‐0.35 to ‐0.10) which effect remained significant over 3‐11 months (SMD ‐0.80, 95% CI ‐1.03 to ‐0.56) and 12 or more months (SMD ‐0.12, 95% CI ‐0.22 to ‐0.01) of supplementation, for those from North America / Europe / Australia (SMD ‐0.07, 95% CI ‐0.11 to ‐0.03), and for those with mild cognitive impairment (SMD ‐0.51, 95% CI ‐0.81 to ‐0.22). B vitamins also showed a significant benefit on episodic memory (SMD ‐0.23, 95% CI ‐0.35 to ‐0.10). Antioxidant and vitamin D revealed no significant benefit on cognitive function compared to control groups.

Conclusion

Our findings indicated that B vitamins might have a therapeutic effect on global cognitive function and episodic memory domain. More life‐span studies are warranted to identify the most effective timing and duration of the vitamin supplementation.
Habitual consumption of fruit, folic acid and cobalamin as risk/protection factors for the incidence of dementia: Data from the "InveCe.Ab" study
Authors: Davin Annalisa , Ceretti Arcangelo , Mimmi Maria Chiara , Cereda Cristina , Guaita Antonio
Published: December 2020

Background

The role of diet as a modifiable factor that may affect the incidence of dementia is currently under investigation. The diet effect could be mediated by blood level of Folic Acid and Cobalamin, whose low levels are recognized as risk factors for dementia. The aim of this work is to evaluate the effects of habitual fruit intake, Cobalamin and Folic Acid on the cumulative incidence of dementia over a period of 4 years in elderly people free of basal dementia.

Method

The subjects were 1321 people born between 1935‐39, enrolled in 2010 by the "InveCe.Ab" study (ClinicalTrials.gov ID: NCT01345110). The cohort was re‐evaluated in 2014 and the onset of dementia was ascertained. The association between fruit consumption and metabolic parameters with dementia at baseline was analyzed with t‐test for quantitative variables and with Pearson chi‐square for qualitative variables. The risk/protection effect of habitual fruit consumption and metabolic mediators on the onset of dementia after 4 years was evaluated by multiple logistic regression.

Result

988 subjects were included in the analysis, The new cases of dementia between 2010 and 2014 were 50. The high habitual fruit consumption was inversely associated with dementia incidence (p = 0.007) and also directly associated with higher levels of Folic Acid (p < 0.005). Women had higher levels of Folic Acid and Cobalamin (p < 0.001) and a tendency towards higher fruit consumption (p = 0.06). The logistic model using Folic Acid, Cobalamin, and sex as covariates, shows that the usual consumption of fruit reduces the 4‐year risk of developing dementia, (OR: 0.421; 95% CI: 0.213‐ 0.831) with a significant interaction between fruit consumption and Folate (OR: 0.771; 95% CI. 0.607‐0.980). Furthermore a higher level of Cobalamin results protective versus dementia.

Conclusion

Our data show that in a population of 70‐75 years the cumulative incidence of dementia is significantly reduced by habitual fruit consumption independently of the plasma levels of Cobalamin. Folate could be the metabolic mediator of this protection.
A synthetic control arm from observational data to estimate the background incidence rate of an adverse event in patients with Alzheimer’s disease matched to a clinical trial population
Authors: Blondeau Kathleen , Schneider Andres , Ngwa Innocent
Published: December 2020

Background

Identifying a potential safety issue in Alzheimer’s disease (AD) clinical trials is challenging due to the blinded nature of the studies and the number of adverse events (AEs) that occur in this patient population independent of the investigational treatment. An accurate estimate of the incidence rate of an AE in nontreated individuals with AD may help to identify unexpected safety findings.

Method

The objective of this retrospective case‐control study was to generate a synthetic control arm from observational data to estimate the background incidence rate of one AE (pneumonia) in individuals with AD. We used high‐dimensional propensity scoring to match individuals aged 50 to 89 years with AD with to controls from 01/01/2014 to 31/12/2018 in PharMetrics, a US claims database. The inclusion and exclusion criteria were matched to a Phase III clinical trial in AD evaluating crenezumab. Additional inclusion criteria included at least two diagnoses of AD using ICD‐9/ICD‐10 in 90 days and ≥90 days of continuous enrollment prior to the index date. The main outcome was the 5‐year incidence rate of pneumonia in patients with AD. A zero‐inflated Poisson model was designed to predict the expected count of pneumonia as a function of AD diagnosis, propensity score, patient age at index date, sex, disease history, and comorbidity using the Charlson Comorbidity Index.

Results

In our preliminary analyses, 31,107 individuals with AD were identified from the database; 19,457 (63%) were female; mean age was 75.7 (SD, 8.3) years. Within 5 years of the reported date of AD diagnosis, 4,692 patients were diagnosed with pneumonia. The incidence rate (95% CI) of pneumonia in individuals with AD was 113.07 (109.84‐116.31) per 1,000 patient‐years. Increasing age (incident rate ratio [IRR], 1.06), being male (IRR, 1.5), and patient comorbidities (IRR, 1.25) were associated with an increased risk of pneumonia in individuals with AD.

Conclusion

A synthetic control arm from observational data may help to estimate the background incidence rate of one AE, pneumonia, in individuals with AD and can help to identify a potential safety issue in a blinded clinical trial.
A prospective long‐term study of TDP‐43 pathology in Alzheimer’s disease aggression
Authors: Vik‐Mo Audun Osland , Hortobagyi Tibor , Módis László , Aarsland Dag
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) in dementia is a major challenge for the health‐care system with a lack of effective treatment strategies. Especially agitation and aggression are pivotal as they represent a large part of the health and social care costs of dementia. But the mechanisms of agitation and aggression are still largely unknown. Comorbid TDP‐43 pathology is common in AD, and here we wanted to explore the association of TDP‐43 pathology and agitation and other NPS in Alzheimer’s disease (AD) and Lewy body dementia (LBD).

Method

From a cohort of 223 patients with dementia who were followed annually for up to 12 years with the Neuropsychiatric Inventory to assess agitation, aggression and psychotic symptoms, post‐mortem standardized semi‐quantitative assessments of TDP‐43 were performed in 47 patients.

Result

In AD (n = 31) patients with aggression had more severe TDP‐43 pathology than those without aggression (p < 0.05). In LBD (n = 16) no significant associations between pathological scores and aggression or psychotic symptoms were found.

Conclusion

TDP‐43 may be a possible mechanism behind aggression in AD and its relation to neuropsychiatric symptom in AD needs further investigation. The description of Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) as a separate disease entity highlights the importance of limbic TDP‐43‐pathology in dementia, and TDP‐43 is a potential drug‐target. Cannabidiol (CBD) has shown effect on TDP‐43 pathways, and preliminary studies have suggested that cannabinoids may improve pain related to neuropathy, spasticity, and psychotic symptoms, which are all associated with aggression in dementia. We are planning Cannabidiol in Alzheimer’s disease Aggression (CanADA); a randomized control trial from 3 centers in Norway.
Measurement of CSF core AD biomarkers for routine clinical diagnosis: Do fresh vs frozen samples differ?
Authors: Bellomo Giovanni , Cataldi Samuela , Paciotti Silvia , Parnetti Lucilla
Published: December 2020

Background

Cerebrospinal fluid amyloid‐beta (Aβ) 1‐42/1‐40 ratio, threonine‐181‐phosphorylated‐tau (p‐tau) and total‐tau (t‐tau) represent core AD biomarkers. The wide availability of automated platforms has represented a high achievement for reducing the pre‐analytical variability of these determinations in routine clinical setting. With respect to classical manual ELISAs, these platforms give us also the possibility to measure any single sample and to get the result within approx. 30 min. So far, reference values are represented by measurements obtained in frozen samples. In this work, we wanted to check if the values obtained in fresh CSF differ from those obtained in frozen samples. This issue could be crucial in routine diagnostic work.

Method

Thirty‐seven consecutive CSF samples have been analyzed immediately after lumbar puncture and after one‐month deep freezing (‐80°C). As automated platform we used LUMIPULSE G600‐II. The fresh aliquot has been analyzed in its storage tube.

Result

As shown in Table 1, in fresh samples an increase of Aβ1‐40, Aβ1‐42 and t‐tau was observed as compared to frozen samples. Aβ1‐42/Aβ1‐40 ratio and p‐tau – ie, the mandatory parameters for diagnosis of Alzheimer disease ‐ showed no variations. With respect to the AD profile according to the A/T/(N) criteria for AD diagnosis (Jack et al., 2018), no changes in classification were observed when comparing results obtained in fresh vs frozen samples.

Conclusion

No differences in Aβ1‐42/Aβ40 ratio, p‐tau and t‐tau were observed in fresh vs frozen samples. According to these data, it seems not necessary to define new cut‐offs for fresh samples. Nevertheless, further larger and multi‐center investigations are needed to confirm these data.
Predicting development of AD clinical symptoms and their progression through a collection of novel plasma Aβ immunoassays
Authors: Liu Lei , Stern Andrew , Dang Yifan , Ostaszewski Beth , Chhatwal Jasmeer P. , Selkoe Dennis J
Published: December 2020

Background

For many years, fluid biomarkers for amyloid β‐protein were described exclusively for Aβ42 and Aβ40, with Aβ40 being the major secreted form and Aβ42 being the predominant component of amyloid‐plaques in AD brain. However, the C‐termini of these two Aβ peptides and the N‐terminus of the AICD are not aligned. It is now clear that secreted Aβ peptides are produced along two proteolytic pathways by γ‐secretase: Aβ49→46→43→40→37 and Aβ48→45→ 42→39/38. We now asked whether a more comprehensive analysis of Aβ peptides in plasma and CSF will help understand and predict brain amyloid pathology and its consequences.

Method

We designed novel immunoassays to detect essentially all the secreted forms of Aβ (Aβ x‐37, 38, 39, 40, 42 and 43), initially on the MesoScale‐Discovery platform (sensitive enough for human CSF samples). To measure same analytes in plasma, we built ultrasensitive immunoassays on the Quanterix SP‐X planar platform with 10‐20 folds enhanced sensitivity. We term Aβ37‐39 short and 40‐43 long Aβs.

Result

We quantified 6 Aβ‐variants in 79 CSF samples from Mayo‐Clinic divided into three diagnostic groups: cognitively normal (CN), mild cognitive impairment (MCI) and Alzheimer's disease (AD). In contrast to Aβ42/40, the short/long Aβ ratios in CSF distinguished CN from AD & MCI more effectively, with AUC (ROC‐analysis) of 0.9609 for Aβ37/42 in distinguishing CN and AD, while AUC is 0.8623 for Aβ42/40. Moreover, both 37/42 and 38/43 correlated significantly with the MMSE scores of these subjects. Next, we tested 88 plasma samples from same cohort, the Aβx‐37/1‐42 ratio in plasma clearly distinguished AD and CN (AUC of 0.8572), while the traditional Aβ1‐42 analyte could not. Currently, we are testing the Aβ37/42 and other ratios in a longitudinal Harvard‐Aging‐Brain‐Study (HABS) cohort.

Conclusion

Compared to the classic Aβ42/40 ratio in CSF or the Aβ1‐42 absolute level in plasma, a comprehensive analysis of Aβ peptides in plasma and CSF yields better Aβ biomarkers to distinguish CN and AD. Moreover, both 37/42 and 38/43 ratios in CSF correlated significantly with MMSE scores. Importantly, we are assessing whether plasma Aβ37/42 correlates most tightly with the development of AD clinical symptoms and their progression, using longitudinal aging cohorts.
Identification of blood eQTLs for AD risk loci
Authors: Bradley Joseph , Deming Yuetiva , Li Zeran , Harari Oscar , Saef Benjamin , Budde John P. , Wang Fengxian , Farias Fabiana H.G. , Davenport Richard ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), Cruchaga Carlos
Published: December 2020

Background

Alzheimer’s disease (AD) is the sixth leading cause of death in the US and most common form of dementia, affecting an estimated 5 million individuals. Currently there are no publicly available treatments for clinical or pre‐clinical symptoms of AD as well as there is high number of genetic variants involved in the onset and progression of the disease. The Alzheimer’s disease Neuroimaging Initiative (ADNI) aims to determine imaging, clinical and genetic biomarkers for early detection and treatment of AD. The goal of this study was to identify blood eQTLs for the genes located under the GWAS loci for AD risk.

Method

The expression data, collected and RMA normalized by ADNI, was captured by the Affymetrix Human Genome U219 Microarray. The data were normalized, trimmed to 500 genes within known AD risk gene regions, and used with GWAS data in multivariate linear regression of European individuals. These analyses can help to identify the functional variant and gene driving the original association.

Result

Our analysis found genome‐wide eQTLs for over 200 genes (∼600 including all isoforms) across the genome.

Conclusion

These results suggests that these variants may play a role in the onset and progression of AD; however, further analysis associating these variants with case/control status, age at onset, and differential expression would be necessary to further verify this. We may also speculate from these data that AD risk loci where we could not find eQTLs play a much stronger functional role in AD onset.
AmyloidIQ: An advanced analytical algorithm to quantify amyloid‐PET [18F]NAV4694 scans
Authors: Rizzo Gaia , Whittington Alex , Hesterman Jacob , Gunn Roger N
Published: December 2020

Background

The global amyloid‐β (Aβ) burden in Alzheimer’s disease (AD) is routinely quantified from static amyloid PET scans using SUVR. We have previously used AmyloidIQ to analyse over 3000 18F‐Florbetapir, 18F‐Florbetaben and 18F‐Flutemetamol scans. These analyses demonstrated that the outcome measure amyloid load (AβL) derived from AmyloidIQ is more powerful than SUVR in cross‐sectional and longitudinal analyses (Whittington et al. 2018 JNM) as well as having a better agreement with visual reads (Whittington et al. HAI 2019). In this work, we extend the AmyloidIQ methodology to [18F]NAV4694 images downloaded from the Global Alzheimer's Association Interactive Network (GAAIN) website (http://www.gaain.org).

Method

AβL is automatically calculated by the AmyloidIQ algorithm from an individual Aβ‐PET scan using voxel‐wise regression with two canonical images that represent non‐displaceable and specific binding signals. The canonical images were derived from 18F‐Florbetapir ADNI data (Whittington et al. 2018 JNM). A composite SUVR was also calculated for each scan. 52 [18F]NAV4694 scans (35 healthy controls, HC, 10 mild cognitive impaired, MCI, and 7 AD) were obtained from GAAIN. The effect sizes (Hedges’ g) between HC and AD patients, and between HC and AD/MCI of AβL and SUVR were compared in [18F]NAV4694 cross‐sectional data.

Result

The AmyloidIQ algorithm was successfully extended to [18F]NAV4694 data with accurate characterization of the data obtained with the previously derived canonical images, now demonstrating its applicability to four different Aβ tracers (Figure 1). In this small sample dataset the cross‐sectional analysis showed that, AβL had similar performance to SUVR (effect size between non‐HC patients and HC was 2.29 for AβL and 2.32 SUVR, and between HC and AD patients was 4.41 for AβL and 4.90 for SUVR). In previous works, AβL has shown better agreement with visual reads than SUVR (Figure 2) and more power in cross‐sectional analysis (Figure 3) with an average increase in effect size of 44% and 21% compared to SUVR for [18F]Florbetapir and [18F]Florbetaben respectively.

Conclusion

AmyloidIQ is a powerful algorithm that has been successfully applied to four different Aβ tracers and that can be used for stratification. A larger sample is required to determine whether AmyloidIQ is more powerful than SUVR for [18F]NAV4694.
Antineuronal antibody prevalence in Alzheimer dementia
Authors: Koertvelyessy Peter , Teegen Bianca , Stoecker Winfried , Düzel Emrah , Glanz Wenzel , Bittner Daniel , Vielhaber Stefan , Diekaemper Elena , Pruess Harald
Published: December 2020

Background

The prevalence of antibodies against neuronal epitopes (nAB) in CSF and serum of Alzheimer dementia (AD) patients is unknown, as is the potential contribution to pathomechanisms influencing the clinical picture parallel to neurodegeneration.

Method

We screened CSF and serum of 164 AD patients and 29 control patients suffering from depression with cognitive impairment. 36 known nAB were examined using cell‐based immunoassays (EUROIMMUN, Germany). Every sample was also examined for as yet undefined nAB using native brain slices of hippocampus and cerebellum. We compared standard CSF parameters and biomarkers of neurodegeneration (commercial ELISA kits, Fujirebio, Ghent, Belgium) between nAB‐positive and negative AD patients and controls. A pathological finding is defined for each nAB reaching or exceeding a predefined, known titer and having a corresponding binding pattern as seen on native hippocampus and/or cerebellum.

Result

We found nAB in 20.1% (33/164) of the AD patients’ serum with 1.8% (3/164) having pathological findings (1*IgG NMDAR, 1*Homer3 and 1*GABAbR antibodies). 2 AD patients had the same nAB in CSF and serum, no nAB was found in CSF alone. Three out of the 29 control patients had nABs but noone had pathological titers.

There was no difference between nAB‐positive and nAB‐negative AD and controls regarding the biomarkers and standard CSF parameters in one‐way ANOVA (see Figure 1 for details and Figure 2 as an overview).

Clinical records of the 3 nAB‐positive AD patients with pathological findings showed normal CSF parameters and biomarkers without signs of abnormal neurological findings with a mean follow‐up of 37 months (ranging from 14‐54 months).

Conclusion

This is the largest study on nAB prevalence in AD using the largest nAB panel so far. In general, prevalence of nABs is high in AD patients. Three patients out of all 193 patients (AD+controls) had pathological nAB findings. Follow‐up of the medical records over more than three years did not reveal aberrant clinical courses. CSF parameters and biomarkers of neurodegeneration did not show any difference between nAB‐positive and ‐negative patients. Patients were not treated with immunosuppressive therapy and therefore the potential impact of the nAB on the clinical picture will require further studies.
Neuroprotective effect of taurine on human neuroblastoma under induced stress
Authors: Rossato Rafaella Carvalho , Pinto Jessica Cristina , de Oliveira Moraes Carlos Dailton Guedes , Salles Geisa Nogueira , Pacheco‐Soares Cristina
Published: December 2020

Background

High concentrations of hydrocortisone is known to cause oxidative stress in neural cell, impairing damage repair and, consequently, triggering cell death. This represents one of the mechanisms of Alzheimer's Disease (AD). To prevent oxidative stress, novel studies have demonstrated neuroprotective effects of taurine in specific concentrations, regulating brain activity, maintaining the integrity of neural membrane and controlling calcium homeostasis, thus preventing cell death by preventing oxidative stress.

Method

First, SH‐SY5Y (human neuroblastoma) cells were incubated with different concentrations of taurine (0.25 to 1 mg/mL), then, after 24h, cells were exposed to 200 µM of hydrocortisone for another 24h (a stablished concentration that reduces SH‐SY5Y viability and induces oxidative stress). Cell viability was evaluated by crystal violet technique. Cells not exposed to hydrocortisone or taurine were used as control.

Result

A concentration curve of taurine was performed (0.25 to 1 mg/mL), demonstrating that the compound stimulates SH‐SY5Y cell growth at 0.5 mg/mL (p = 0.0457) (Figure 1A). This concentration was stablished as protective. To verify the neuroprotective potential, cells were pre‐treated with 0.5 mg/mL of taurine and then exposed to 200 µM of hydrocortisone. Importantly, cytoviability was not only preserved but also statistically improved, compared to the control group (p < 0.0001) (Figure 1B).

Conclusion

In high concentration (200 µM), hydrocortisone induces oxidative stress in SH‐SY5Y, an important pathway observed in AD. Once cells are pre‐incubated with 0.5 mg/mL of taurine followed by 200 µM of hydrocortisone exposure, cytoviability is preserved and stimulated, representing a considerable step to further evaluate taurine as a significant neuroprotective tool for AD. (1) Moraes, C.D.G.O. et al. Genotoxic effects of photodynamic therapy in laryngeal cancer cells–An in vitro study. Experimental Biology and Medicine, v. 244, n. 3, p. 262‐271, 2019. (2) Salles, G.N. et al. Prolonged Drug‐Releasing Fibers Attenuate Alzheimer’s Disease‐like Pathogenesis. ACS applied materials & interfaces, v.10, n.43, p.36693‐36702, 2018. (3) Sergeeva, O.A. et al. Taurine‐induced long‐lasting enhancement of synaptic transmission in mice: Role oftransporters. The Journal of physiology, v.550, n.3, p.911‐919, 2003. (4) ROSSATO, R.C. et al. Hydrocortisone cytorestores oxidative stress‐induced neuroblastoma. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 15(7), p.642, 2019.
Novel small chemical compound with NFAT modulatory properties alleviates synaptic dysfunction and improves cognition in mouse models of amyloid pathology
Authors: Sompol Pradoldej , Gollihue Jenna L. , Cloyd Ryan , Koren Shon , Nation Grant K. , Abisambra Jose F. , Artiushin Irina A. , Kraner Susan D. , Huzian Orsolya , Hackler Laszlo , Puskas Laszlo G. , Norris Christopher M.
Published: December 2020

Background

Hyperactivity of the protein phosphatase calcineurin (CN) in brain directly corresponds to key neuropathological and clinical features of Alzheimer’s disease (AD). While inhibition of CN ameliorates pathophysiologic and cognitive changes in mice with AD‐like pathology, concerns over adverse effects have slowed the transition of common CN‐inhibiting drugs to the clinic for treatment of AD and AD‐related disorders. Targeting substrates of CN, like the nuclear factor of activated T‐cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that modulates NFAT signaling, without inhibiting CN activity.

Method

Cell culture studies — Rat cortical astrocyte cultures were treated with a variety of pathogenic factors in the presence of Q134R or the CN inhibitor, cyclosporine. NFAT‐dependent luciferase activity and dephosphorylation of non‐NFAT substrates were assessed. Intact mouse studies — Q134R was delivered (via oral gavage) to APP/PS1 mice at different ages, or to wild type (WT) mice infused with oligomeric amyloid‐beta peptides. Cognition was assessed on a Y maze along with several postmortem measures including NFAT4 activity, glial activation (GFAP and Iba‐1 expression), amyloid deposition, long‐term survival, and synaptic function and plasticity.

Result

In primary astrocytes, Q134R significantly inhibited NFAT activation in a concentration‐dependent manner, but did not inhibit the CN‐dependent dephosphorylation of non‐NFAT substrates in vivo or in vitro. Short‐term treatment of APP/PS1 mice with Q134R inhibited the nuclear translocation of NFAT4 in hippocampal astrocytes while causing a significant drop in GFAP volume, a mild reduction in Iba1, and no change in amyloid pathology. Short‐term treatment with Q134R also improved cognitive function in APP/PS1 mice and amyloid‐infused WT mice. Long‐term oral delivery of Q134R over many months promoted survival in WT mice and improved synaptic function and plasticity in APP/PS1 mice.

Conclusion

Q134R has novel CN‐independent, NFAT modulatory properties and improves key neurologic function parameters in mouse models of AD‐like pathology. The results suggest that Q134R is a promising drug for treating AD and AD‐related disorders.
Leveraging amino acid sensors as therapeutic targets for tauopathies and related dementias
Authors: Lee Daniel C. , Ma Chao , Morgan Dave , Liang Huimin , Kovalenko Andrii , Sandusky‐Beltran Leslie A. , Calahatian John Ivan , Kallupurackal Mani , Hunt Jerry B , Pandey Shalini , Blazier Danielle , Bickford Paula , Michalski Camilla , Fahnestock Margaret , Pedersen Daniel Sejer , Brauner‐Osborne Hans , Ulven Trond , Selenica Maj‐Linda B.
Published: December 2020

Background

Tauopathies including Alzheimer’s disease (AD) comprise of over 27 neurodegenerative diseases. Our group has uncovered a unique interaction between uncoupling of amino acid sensors and tauopathies. L‐Arginine metabolism impacts multiple processes that seemingly show considerable influence upon tau biology. Several protein sensors have been identified that sense arginine within the lysosomal lumen, cytoplasm and signal to the mechanistic target of rapamycin complex 1 (mTORC1). GPRC6a, g‐protein coupled receptor also senses arginine levels but also signals to mTORC1. We posit that GPRC6a remains tonically active through extracellular arginine. GPRC6a signaling increases during tauopathies and thereby promotes hyper‐mTORC1 activation and impairs autophagy flux.

Method

We performed PCR‐array analysis, biochemical analysis for gene transcripts and protein expression for Alzheimer’s disease brain tissue and aged matched controls. We performed a series of mechanistic studies on GPRC6a and tau biology using siRNA, shRNA, drug pharmacology in cell culture models and (PS19 tau mice) or wild‐type littermates. RNA seq was performed on GPRC6a knockout mice crossed with PS19 mice.

Result

Our work indicates dysregulation of gene transcripts for arginine sensors, components of mTORC1 signaling in Alzheimer’s disease (AD) brains and mice with tauopathy. AD brains and tau PS19 mice showed increased GPRC6a, CASTOR1 and SLC38A9 signifying dysfunction in arginine sensing. Tau PS19 mice showed increased total and extracellular arginine in the brain, which further increased with neuronal activity. GPRC6a gene repression or novel allosteric antagonists decreased mTORC1 activation and reduced tau burden. Conversely, GPRC6a overexpression increased mTORC1 and tau accumulation. Knockout mice for GPRC6a crossed with PS19 tau transgenic mice reversed tau‐induced mRNA signatures in the brain via RNA seq. Microglia and neurometabolism were most affected in GPRC6a knockout mice signifying a critical role for arginine sensors in microglia during tau deposition. Importantly, novel allosteric antagonists to GPRC6a increased microglia phagocytosis and index.

Conclusion

Our work identifies a new pathway activated in AD and models of tauopathy yet provides the discovery of a new class of agents that govern microglia function, autophagy and neurometabolism. These data provide new therapeutic strategies for proteinopathies that exploit nutrient sensing dysfunction in AD.
Integrating human brain proteomes and genome‐wide association results implicates new genes in Alzheimer’s disease
Authors: Wingo Aliza P. , Liu Yue , Gockley Jake , Logsdon Benjamin A. , Duong Duc , Dammer Eric B. , Robins Chloe , Cutler David J. , De Jager Philip L. , Lah James J. , Bennett David A. , Levey Allan I. , Seyfried Nicholas T. , Wingo Thomas S.
Published: December 2020

Background

Alzheimer’s disease (AD) is the most common type of dementia, and it has a substantial genetic basis. Recent AD genome‐wide association studies (GWAS) continue to expand the number of loci that are significantly associated with AD; however, how those loci confer risk for AD remains unclear. Here, we addressed this problem by integrating 376 deep human brain proteomes and 888 human brain transcriptomes with recent AD GWAS results to identify genes, transcripts, and proteins that likely contribute to AD pathogenesis.

Methods

We inferred the genetically controlled portion of protein abundance using 376 deep human brain proteomes, and these results were integrated with two recent large AD GWAS results that included 455,258 participants (Jansen et al 2019), and 82,771 participants (Kunkle et al 2019), respectively, using the FUSION pipeline (Gusev et al 2016). We performed an analogous analysis using 888 human brain transcriptomes to infer the genetically controlled portion of the transcript abundance and integrated those results with the aforementioned AD GWAS results.

Results

We identified a total of 15 genes whose genetically regulated brain protein abundances were associated with AD. They are ACE, CARHSP1, CTSH, DOC2A, EPHX2, ICA1L, LACTB, MADD, PITPNC1, PLEKHA1, PVR, RTFDC1, SNX32, STX4, and STX6. At the transcript level, we identified a total of 49 genes whose cis‐regulated mRNA expression levels were associated with AD. Of the 15 genes identified at the protein level, 33% (5 of 15) were also identified at the transcript level. Furthermore, 73% of these 15 genes identified at the protein level were highly expressed in excitatory neurons based on a reference single‐cell RNA‐sequencing dataset from human brain. In an independent replication dataset using single‐shot label‐free proteomes (n = 205), only one of the 15 proteins were measured and imputed (EPHX2). We replicated EPHX2’s association with AD in that dataset.

Conclusion

Together, our findings implicate 15 human brain proteins in the pathogenesis of AD and suggest that these proteins are controlled by both transcriptional and post‐transcriptional mechanisms. Our results lay a foundation for future mechanistic studies to develop novel treatments and biomarkers for AD.
Automatic analysis of Alzheimer’s disease: Evaluation of eye movements in natural conversations
Authors: Perez Arlen , Ratté Sylvie
Published: December 2020

Background

Among the studies concerned with the description of changes in nonverbal communications, some authors have established a link between eye movement and AD [1]. In this presentation, we introduce a method to automatically analyze and evaluate the performance of AD patients during natural conversations through eye movements. This project was conducted as part of a research program funded by Natural Sciences and Engineering Research Council of Canada ( "Pattern recognition for the detection and monitoring of verbal and non‐verbal alterations in Alzheimer's disease", RGPIN‐2018‐05714).

Method

We analyzed 22 videos in the Carolinas Conversations Collection, a dataset where conversations with elderly people were recorded. These videos have 370 minutes approximately, with 17 subjects, 9 healthy controls (HC), and 8 AD patients. We tracked the eye movements through time in two ways, as a vector [Figure 1] and as landmarks on the eyes [Figure 2]. Then we trained classifiers to distinguish HCs and AD subjects, and performed the experiments using gaze vectors and eye landmarks as features (individually, combined).

Result

We obtain the performance of the classifiers measuring the accuracy, precision, recall, and ROC curve. Our results show that the combination of eye landmarks and gaze vectors features is strongly related with the AD condition. The classification sensitivity (ROC) is 77% performing with gaze vector features, 85% using the eyes landmarks in 3D, and combining both, we obtained 88% sensitivity (HC vs. AD) [Table 1].

Conclusion

The automatic analysis of the eye movements could be a useful tool for clinicians and researchers studying early signs of AD. In future work, we will analyze facial expressions in order to study the link between verbal features (related to speech and content) and non‐verbal features (facial expressions, eye movements), and their correlations with AD. [1] Fernández G, Mandolesi P, Rotstein NP, Colombo O, Agamennoni O, Politi LE. Eye movement alterations during reading in patients with early Alzheimer disease. Invest Ophthalmol Vis Sci 2013;54:8345–52. https://doi.org/10.1167/iovs.13‐12877.
Expression of mutant human tau protein drives synaptic loss in Caenorhabditis elegans
Authors: Massengale Molly B. , Gamblin T. Chris , Ackley Brian D.
Published: December 2020

Background

Tau aggregation is associated with many neurodegenerative diseases, and inter‐neuronal neurofibrillary lesions composed of tau are a defining characteristic of various tauopathies, including Alzheimer’s disease. Additionally, mutations in human tau have been linked to several neurodegenerative disorders with varying phenotypic effects. How tau aggregation results in altered neuronal function is complex and not yet fully understood. Animal models are powerful tools to probe tau aggregation‐dependent phenotypes. However, they can take a long time to mature and give phenotypes, are created in different genetic backgrounds and can require death of the animal to visualize outcomes. Thus, new models that can avoid some of these issues can facilitate a better understanding of tauopathies.

Method

We have generated multiple lines of transgenic C. elegans expressing different variants of the longest isoform of human tau (htau40) in neurons to better understand how aggregation might cause subsequent downstream events leading to increased toxicity. We have used synaptic markers to examine the consequences of tau aggregation on synaptic integrity during aging.

Result

When broadly expressed throughout the nervous system an aggregation prone htau40 variant (3PO) or an FTDP‐17 associated mutation (P301L) resulted in decreased lifespan, as well as a decreased locomotor capability as animals aged. Decreased lifespan, along with cognitive and motor defects, are associated with human tauopathies, suggesting our model is reproducing consequences relevant to human disorders. When we selectively express mutated htau40 in the GABAergic motorneurons, we find an age‐associated decline in the number of GABAergic motor neuron synapses, importantly, in the absence of other indicators of neuronal degeneration, i.e. axons and cell bodies were still intact. We have also begun testing mutations in C. elegans orthologs of known Alzheimer’s risk factors and found that loss of the LAR‐like receptor tyrosine phosphatase enhances the synaptic loss due to mutations in htau40.

Conclusion

C. elegans models of tauopathies permit an analysis of synaptic phenotypes in living animals. Our model can be used to probe both tau variants and other genetic modifiers to better understand how tau aggregation impacts neuronal homeostasis and function.
A transcriptional mechanism for retromer misregulation
Authors: Roque Cláudio Gouveia , Baleriola Jimena , Hengst Ulrich
Published: December 2020

Background

Transcription factors (TFs) regulate gene expression and define cellular homeostasis. This occurs via poorly resolved combinations of TFs that synergistically coordinate transcriptional decisions (Lambert et al., 2018). TFs are also drivers of pathology (Lee and Young, 2013), as aberrant transcriptional changes commonly develop in disease states. Recent transcriptomic profiles of the Alzheimer’s disease (AD) brain indicate that specific groups of genes become deregulated during the course of disease progression (Mathys et al., 2019; Small et al., 2005; Zhang et al., 2013), highlighting the need to understand how TF‐mediated mechanisms of gene expression fail during AD pathogenesis.

Method

Cellular models of disease counterpointed with analyses of AD postmortem tissue that employed a combination of DNA‐, RNA‐, and protein‐based approaches.

Result

We report the characterization of a transcription factor heterodimer linked to Alzheimer’s disease (AD). This complex is enriched in the dorsolateral prefrontal cortex of late‐onset AD patients and functions as a sensor of β‐amyloid stimuli in neurons. We additionally identify the retromer, a master orchestrator of endosome sorting and amyloid precursor protein metabolism (Small and Petsko, 2015), as an AD‐relevant transcriptional target of this heterodimer, and connect its accumulation in AD to disrupted retromer gene expression.

Conclusion

Our findings support a mechanism of retromer dysfunction promoted by an AD‐associated transcriptional pathway. Conceptually, they also argue for the importance of probing TF interactions as a way to understand gene expression, both in normalcy and during disease pathogenesis.