bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein levels of APP, ADAM10 and BACE1 in aging adults with Down syndrome: Preliminary findings
Authors: Bram Jessyka Maria de França , Talib Leda Leme , Joaquim Helena Passarelli Giroud , Gattaz Wagner Farid , Forlenza Orestes Vicente
Published: December 2020

Background

Down syndrome (DS) is associated with high prevalence of dementia, with onset in late adulthood. Given the pathological similarities, dementia in DS is regarded as a variant of early‐onset Alzheimer’s disease (AD). The genetic causality of dementia in DS is attributed to the overexpression of the amyloid precursor protein (APP) gene located on chromosome 21. Abnormalities in the regulation of APP metabolism cause the overproduction of the amyloid‐beta peptide (Aβ) and subsequent effects on the amyloid cascade, which ultimately lead to the formation of neuritic plaques and neurofibrillary tangles. To compare protein levels of secreted APP metabolites (sAPP) and APP‐secretases (ADAM10, BACE1, PSEN1) in platelets from adults and elders with DS compared to controls, and to determine whether these findings correlate with global cognitive state.

Method

The study group comprises 21 aging adults with DS, and the comparison group comprises a similar number of age/gender‐matched healthy subjects with normal karyotype (controls). DS subjects were subdivided according to age stratification (20‐34 years, n=8; 35‐49 years, n=4; ≥50 years, n=9). Global cognitive state of participants was ascertained with the CAMCOG schedule (controls) or its adapted version for DS (CAMCOG‐DS). Protein levels of APP‐related biomarkers were determined by Western Blotting.

Result

CAMCOG‐DS scores were significantly different in DS subgroups (clinical evidence of cognitive impairment/dementia, DSd; normal cognitive function, DSnc). DSd subjects achieving lower scores (43.8, SD20.7) than DSnc (66.4, SD16.1) p=0.001. Low levels of APP130 have been found among DS as age increased (1.71, SD0.99; 0.76, SD0.46; 0.48, SD0.16, respectively; p=0,013), and higher BACE1 levels was found between aged 35‐49 years old DS (0.44, SD0.77) compared with aged 20‐34 years old DS (0.70, DS0.20), p=0,048. No statistically significant differences were found in platelet levels of ADAM10.

Conclusion

In this preliminary analysis, APP‐related platelet biomarkers was able to show significant differences among DS age groups.
Connectivity between serotonin and dopamine systems is altered in Alzheimer’s disease
Authors: Ceyzériat Kelly , Gloria Yesica , Millet Philippe , Tournier Benjamin
Published: December 2020

Background

Approximatively half of Alzheimer’s disease (AD) patients shows dysfunctions of the dopaminergic (DA) and serotoninergic (5HT) systems, in addition to cognitive impairment. However, the relationships between AD and the time of onset of monoaminergic disorders and their course remain poorly understood. In the present study, we characterized the DA system and the links between the 5HT and the DA systems in the TgF344‐AD rat model of AD.

Method

Locomotor activity tests were performed in response to the dopamine receptor 2 (D2R) agonist quinpirole. Quinpirole decreases and activates locomotion according to the dose used, which is attributable to an effect at the pre‐ and post‐synaptic D2R, respectively. The impact of the serotonin receptor 2A (5HT2AR) antagonist MDL100.907 on the quinpirole‐induced locomotion changes was also tested. In vivo SPECT molecular imaging with [123I]IBZM was used for the indirect measurement of DA release in the striatum in response to MDL100.907. The densities of D2R and 5HT2AR receptors were evaluated by in situ autoradiography.

Result

Quinpirole stimulated locomotion in wild type (WT, +114, +170 and +65%, at 6‐, 12‐ and 18‐months) and this effect is increased in TgF344‐AD rats at all ages (+340, +300 and +103%). TgF344‐AD rats also showed an increased response to pre‐synaptic dose of quinpirole, at both 6‐ and 12‐months old. These data demonstrated a hypersensitivity of the D2R. The administration of MDL100.907 significantly exacerbated the quinpirole‐induced locomotion in WT (+40%) but not in TgF344‐AD rats, indicating a hypo‐sensitivity of the 5HT2AR. The striatal dopamine release in response to MDL100.907 was significantly higher in WT (25.6%) than in TgF344‐AD rats (10.3%), showing a reduction of the DA system control by the 5HT2AR. This effect was measured at an early stage of the disease (6 months‐old), when amyloid plaques and cognitive disorders were still slight. In addition, the density of 5HT2A receptors was decreased in DA system‐related regions (‐27% in striatum and ‐40% in subtancia nigra), without any modifications on the D2R.

Conclusion

TgF344‐AD rats showed functional DA system alterations and a reduction in the connectivity between the 5HT2AR and the DA system that appears early in the course of the disease.
Investigation of herpesviruses in dementia patients and associated inflammatory gene modulation
Authors: Seaks Charles E. , Kloske Courtney M. , Salmeron Kathleen , Nelson Peter T. , Wilcock Donna M.
Published: December 2020

Background

Alzheimer’s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) are the leading causes of dementia worldwide, with the two frequently found co‐morbid in dementia patients at autopsy. Studies have connected multiple herpesviruses to the development and pathogenesis of AD. The goal of this study was to determine the prevalence of four common herpesviruses in a cohort of AD and VCID patients, and to identify differential gene expression as a function of viral presence. We hypothesize AD and VCID cases will possess more latent virus than control cases, and cases with latent virus present will show a down‐regulation of innate immune related genes, and an upregulation of cell survival genes and transcriptional suppressors.

Method

Using droplet‐based PCR, we quantified the prevalence of four herpesviruses (herpes simplex virus 1, herpes simplex virus 2, cytomegalovirus, and human herpes virus 6) in a subset of brain autopsy tissue obtained from the Sanders‐Brown Center on Aging Alzheimer’s Disease Center (UK‐ADC). RNA and genomic DNA was extracted from the superior medial temporal gyrus and cerebellum of 49 cases (n=18 control, n=10 vascular pathology, n=20 AD, n=1 mixed AD+VCI). Genomic DNA was used to determine the presence of latent virus and cDNA to determine actively replicating virus. The RNA from these regions was run on the NanoString neuroinflammatory panel which quantifies a number of genes, ranging from neuroinflammatory markers to cell specific functional genes.

Result

We identified an increased amount of latent viral populations in the AD patients relative to control patients. NanoString analysis supported our initial hypothesis regarding gene regulation relating to innate immunity and cell survival, but we also observed downregulation of insulin‐like growth factor, synapse‐associated protein 97, and cell death‐inducing DFFA‐like effector b in the presence of certain latent viral populations.

Conclusion

Our results demonstrate the prevalence of herpesviruses within an AD cohort, supporting research suggesting a link between the two. Further, it shows alterations in the expression of neuroinflammatory genes as a function of latent virus presence.
Integrative analysis of summary data from GWAS and eQTL studies predicts tissue‐specific gene targets for Alzheimer’s disease
Authors: Shen Li , Yao Xiaohui
Published: December 2020

Background

Genome‐wide association studies (GWAS) have been successful in identifying risk variants for Alzheimer’s disease (AD). However, it is unclear how these genetic variants affect tissue‐specific transcriptomic alternations in AD. The summary data‐based Mendelian randomization analysis (SMR) is a method designed to address this problem. It integrates summary data from independent GWAS and expression quantitative trait locus (eQTL) studies to identify genes differentially expressed between phenotypic groups.

Methods

We performed SMR to predict gene targets differentially expressed in AD, using summary statistics of brain eQTL studies and a landmark AD GWAS. Significant eQTL findings (FDR p≤0.05) of thirteen brain tissues were downloaded from https://gtexportal.org. GWAS summary statistics were obtained from an AD meta‐GWAS: https://ctg.cncr.nl/software/summary_statistics. The linkage disequilibrium (LD) information, required by SMR, were estimated using the ADNI genotyping data (N=1,536). For each tissue, SMR was performed to identify the pleiotropic associations between gene expression data and the AD phenotype. Bonferroni method was used for multiple comparison correction.

Results

Figure 1 shows 64 significant AD‐gene associations identified by SMR, involving 14 genes and 13 brain tissues. Some findings have been studied as top AD genes (BIN1 and CR1), or located around the AD genes (APOC2, PVRIG, STAG3, GPC2). Two genes (HLA‐DQA2 and SNX32) are new candidates that have no SNPs achieving meta‐GWAS p<5.0E‐8 within 20 kb from the gene. HLA‐DQA2 is located in the region of AD risk gene HLA‐DRB1. SNX32 is a novel AD associated gene predicted by SMR. SNX32 is a family member of SNX proteins, and is a component of retromer which has been widely reported for its role in the AD etiology.

Conclusions

Tissue‐specific transcriptomic association analysis using GWAS summary statistics and eQTL data identified genes associated with AD due to pleiotropy. Multiple genes were identified as potential AD targets in various brain tissues, given the estimated pleiotropic associations between their expression levels and AD diagnosis. These identified genes warrant further investigation as potential targets for functional validation to help better understanding of molecular mechanisms of AD.
Developing a novel alpha‐synuclein positron emission tomography (PET) tracer for the diagnosis of synucleinopathies
Authors: Capotosti Francesca , Vokali Efthymia , Molette Jerome , Tsika Elpida , Ravache Myriam , Juergens Tanja , Melo dos Santos Antonio , Darmency Vincent , Piorkowska Kasia , Chauhan Mayank , Kroth Heiko , Hliva Valerie , Sol Olivier , Pfeifer Andrea , Kosco‐Vilbois Marie
Published: December 2020

Background

The progressive accumulation of aggregated alpha‐synuclein (a‐syn) in the form of Lewy bodies and neurites is the hallmark of e.g. Parkinson’s disease (PD). Due to the low density of a‐syn pathology and the frequency of co‐existing proteinopathies in PD (e.g., beta‐amyloid, tau), an a‐syn PET tracer must display high binding affinity and selectivity to the target, as well as minimal background.

Method

[18F]‐ACI‐Cpd‐AE was evaluated in a first‐in‐human (FiH) study. [18F]‐ACI‐Cpd‐AE dynamic PET imaging was conducted over 90 min in five PD subjects (four idiopathic PD, 68.7 years and MDS‐UPDRS III 'off‘ score 43.3, and one with SNCA duplication, 49 years and MDS‐UPDRS III 'off‘ score 52) and five healthy volunteers (HV, 58.4 years). Specific retention of [18F]‐ACI‐Cpd‐AE was evaluated by calculating the distribution volume ratio (DVR) from kinetic analysis with an arterial input function and the standardized uptake value ratios (SUVr) from static analysis, using the middle frontal cortex as reference region. In parallel to the FiH evaluation of [18F]‐ACI‐Cpd‐AE, a thorough medicinal chemistry lead to the design of new promising compounds and the throughput of the screening assays was improved.

Result

In the FiH study, [18F]‐ACI‐Cpd‐AE displayed fast brain uptake, very low non‐specific retention, rapid metabolism and high free fraction. In this small cohort, no significant evidence of cross‐sectional difference between healthy controls and PD subjects was observed. Averaged across target regions the SUVr (30‐90min) range was 1.15‐1.22 in PD subjects and 1.14‐1.28 in HV. Specifically, in left substantia nigra, mean SUVr was 1.32±0.15 in PD and 1.19±0.18 in HV. Based on these clinical data, a new chemical series has been identified to retain affinity and selectivity while improving target occupancy.

Conclusion

In house medicinal chemistry efforts led to the discovery of ACI‐Cpd‐AE, a potential a‐syn PET tracer that binds selectively and with high affinity to a‐syn aggregates. In the FiH study, ACI‐Cpd‐AE demonstrated fast brain uptake and low non‐specific retention. Further analyses of the FiH data and evaluation in patients with expected higher levels of pathological brain a‐syn aggregates will be performed. In parallel, compounds with improved binding properties have been identified and optimized for further development.
Aerobic capacity level can influence spatial navigation performance in healthy and MCI older adults
Authors: dos Santos Sacramento Plácido Jessica , Ferreira Jose Vinicius , Silva Felipe de Oliveira , Araujo Juliana , Laks Jerson , Deslandes Andrea Camaz
Published: December 2020

Background

Spatial navigation is a complex and fundamental cognitive function that emerges as one of the first deficits in patients with Mild Cognitive Impairment (MCI). Successful spatial navigation relies on an interaction between physical and cognition ability. However, the mechanisms of real‐world navigation in this population remain unclear, especially the possible influence of physical performance. Therefore, the objective of this study was to investigate the possible influence of physical variables (balance, mobility and aerobic capacity) on spatial navigation performance of healthy and MCI individuals through the Floor Maze Test (FMT). As a secondary objective, we compare the performance of these elderly and determine which cognitive variables are associated with spatial ability performance on the test

Method

Sixty‐two elderly subjects (>60years) (healthy=39;MCI=23) were evaluated. Spatial navigation was investigated through the FMT, Planning Time (PT), Immediate Maze Time (IMT) and Delayed Maze Time (DMT). Moreover, while physical capacity was assessed through the Sit to Stand, 8 foot up and go and STEP test (Senior Fitness Test Battery), and cognitive functions were examined by MMSE, the clock drawing test, digit span, and Trail (A and B). The relationship and possible association between FMT performance and independent variables were analyzed using regression and correlation models.

Result

The MCI group was significantly slower in all stages of FMT. In addition, FMT performance was mainly associated with spatial orientation and aerobic capacity (R2=0.29 p= <0.001). Logistic regression analysis showed that the elderly with low aerobic capacity is 3 times more likely to have the worst performances at DMT stage even after controlled by age and diagnostic (O.R =3.1 p=0.04).

Conclusion

Healthy and MCI older adults should be encouraged to keeping a physical exercise routine in order to maintain their cardiorespiratory levels and spatial navigation ability. Also, future studies must investigate the temporal relationship among the decline of aerobic capacity, spatial navigation and MCI diagnosis.
Significant biomarkers for predicting depression in patients with Alzheimer’s disease
Authors: Ashraf‐Ganjouei Amir , Sedghizadeh Mohammad Javad , Aghajan Hamid , Vahabi Zahra
Published: December 2020

Background

Depression is considered to be one the most common psychiatric co‐morbidities in Alzheimer’s disease (AD). Besides its prevalence, depression is associated with faster cognitive decline, physical aggression toward caregivers, earlier admission to nursing homes and lower quality of life. Therefore, early prediction of depression and selecting patients with higher risks for developing depression in the course of AD can provide an opportunity for earlier intervention and higher quality of life. This study’s primary intent was to explore the ability of feature selection algorithms to indicate baseline features that can predict the development of depression in AD patients.

Method

We have selected 28 AD patients from The Alzheimer’s Disease Neuroimaging Initiative (ADNI) that developed probable depression in 3‐5 years of follow‐up and 56 age‐ and sex‐matched AD patients without probable depression developed in the course of the disease. We implemented statistical analyses to identify the top significant markers offering the highest f values.

Result

Our results indicated that P‐tau csf level, tau csf level, APOE4 genotype, ECogPtLang score (representing the interference of language impairment reported by the participant) and The Mini‐Mental State Exam (MMSE) score were the best features for predicting the development of depression in AD patients (f values: 7.38, 6.17, 3.96, 3.03 and 2.37, respectively). The first 3 markers possess p values < 0.05.

Conclusion

These results provide primary evidence in favor of a distinguishable baseline profile in AD patients with higher risk for depression in the future. Therefore, caregivers might be able to classify AD patients prone to developing depression based on these features and provide earlier interventions.
Hospital‐associated deconditioning: Brain health issues beyond physical factors
Authors: Chen Yaohua Sophie , Domínguez‐Vivero Clara , Almirall‐Sanchez Arianna , Oz Didem , Romero‐Ortuno Roman
Published: December 2020

Background

Hospital‐associated deconditioning (HAD) or post‐hospital syndrome is a multisystem decline that leads to poor functional performance after acute hospitalization. Although hospitalization is supposed to treat an acute condition and improve the overall outcome, HAD may be significant, especially in older people. Recommendations for the management of HAD still lack, partly due to the poor understanding of the underlying processes. We aim to review existing data on mechanisms, risk factors, natural history, measuring tools, and intervention in HAD, with a specific focus on brain health.

Method

We searched PubMed, sCielo and Cochrane database for relevant articles published between 1 January 2009 and 31 December 2019. Search terms were “post‐hospitalization syndrome” OR “deconditioning” OR “hospital‐associated functional decline” OR “pre‐existing frailty” OR “unrecognized vulnerability”. Three researchers independently selected papers according to title relevance and then re‐checked for abstract relevance.

Results

We first selected 63 studies based on the title relevance and 14 of them were excluded after reviewing the abstract. Research on this field has been mainly led from a physical perspective, in geriatrics or rehabilitation settings. 25 studies were related to mechanisms; 18 to risk factors and trajectories; 10 to measuring and predictive tools and 5 to interventions. Mechanisms referred to the inevitable change imposed by the hospitalization (e.g. reorganization of sensorimotor cortex, maladaptive cognitive schemas, vascular deconditioning) and to the own frail condition of the population at risk. Risk factors varied from older age to nutritional status, mobility or functional status before admission among others. Cognitive impairment, ability for ADLs and IADLs at admission and depression were also predictors of functional decline. Assessment of those items worked as a useful tool to identify vulnerable patients for HAD. Regarding interventions, all but one was devoted to physical rehabilitation and environmental modifications. Only one study focused on cognitive stimulation.

Conclusions

Several studies have focused on HAD in the last decade, with some consistent findings. Cognitive impairment, depression and neurological changes may have a role in hospital deconditioning pathophysiology and may be useful to identify patients and risk. Cognitive rehabilitation and neurological interventions should be evaluated as well in deconditioning prevention and treatment.
The potential role of neuroinflammation and synaptic plasticity for neuropsychiatric symptoms
Authors: Blum Hellen , Lausser Ludwig , von Einem Björn , Fissler Patrick , Kolassa Iris‐Tatjana , Otto Markus , Tumani Hayrettin , Kestler Hans , Rosenbrock Holger , von Arnim Christine
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) show a high prevalence within Alzheimer’s dementia. Evidence from animals and humans suggest a role of inflammatory cytokines and second messengers related to synaptic plasticity such as cGMP in Alzheimer´s disease (AD). In addition, studies show associations of serum interleukins (IL) and cGMP with NPS. However, the role of different ILs and cGMP in the pathogenesis of NPS is still not fully clear and studies on CSF are lacking. This study examines the associations between NPS with different established AD markers, pro‐ and anti‐inflammatory ILs and cGMP in the CSF.

Method

CSF and Serum samples of 120 patients with SCI, MCI or dementia and 19 controls who were previously examined at the memory clinic Ulm were analysed for this study. In clinical routine NPS were assessed by the neuropsychiatric inventory (NPI) total score and the Geriatric Depression Scale‐15 (GDS). Cytokines were determined by MSD V‐Plex assay in serum and CSF of patients, cGMP was determined by ELISA in CSF. Linear and binary logistic regression models were used for investigation. Bootstrapping was used if model assumptions were not fulfilled. Analyses were adjusted for ApoE genotype, age, gender and education. Additionally, an exhaustive screening for predictive marker combinations was performed (NPI>9, yes/no).

Result

The NPI total score was not associated with any of the evaluated ILs, but there was a positive association with CSF‐Abeta‐42 (β = .20, p = .038). Higher cGMP was associated with a lower OR for NPI>9 (OR = 0.69, p = .012). GDS was positively associated with IL‐1RA (β = .20, p = .029). IL‐6 was negatively associated with CSF‐Abeta‐42 (β = ‐0.09, p = .035). The predictive models achieved a maximal accuracy of 67.3%.

Conclusion

This study is one of the first, examining the relationship between CSF inflammatory cytokines, cGMP, AD pathology and NPS in memory clinic outpatients. The results indicate a role of cGMP in NPS. Furthermore, results indicate a potential role of ILs in depression in older adults (IL‐1RA) and in AD. Because of the risk for alpha‐error inflation due to multiple comparisons, further research is needed to replicate these findings.
Robot‐assisted detection of subclinical dementia: Progress report and preliminary findings
Authors: Håkansson Krister , Beskow Jonas , Kjellström Hedvig , Gustafsson Joakim , Bonnard Alexandre , Rydén Marie , Stormoen Sara , Hagman Göran , Akenine Ulrika , Pérez Kristal Morales , Henter Gustav , Sundell Maria , Kivipelto Miia
Published: December 2020

Background

Earlier identification of an underlying AD pathology could increase chances that preventive or curative treatment will be more successful. Human limitations in sensory capacity, attention and parallel processing could mean that automatic and simultaneous registration from several information channels in combination with artificial intelligence processing could advance diagnostic precision and accuracy. Here we report the progress of an interdisciplinary project to develop robot‐assisted diagnostics to detect early neurocognitive disorder.

Method

Behavior in 100 patients without previous evidence of cognitive disorder is recorded during their first clinical examination visit. We record gaze, pupil dilations, skin temperature changes, speech characteristics, mimics, pulse, heart rate variability, and motor activity (see image 1). We then use machine learning to identify behavior signals and signal patterns that can distinguish between persons with and without an underlying neuropathology. In addition, we perform human analysis of recorded video and audio on each patient. Over 40 behavior categories are carefully checked, among them repetitions, irrelevant deviations, hesitations, degree of problem awareness, restlessness and inadequate word usage. This analysis is performed by a semi‐blinded interdisciplinary expert group of clinically experienced physicians, neurologists, speech therapists, psychologists, nurses, and experts in automatic verbal and non‐verbal behavior analysis.

The results from this study will be implemented to further develop a social robot platform (Furhat, see image 2) with adequate sensors and algorithms so that it can interact with patients and assist in the diagnostic process.

Result

Approximately 25 patients have so far been recorded and analyzed. Preliminary results are that the diagnostic prediction by the expert group, solely based on observation of patient behavior from audio and video, fully has coincided with the diagnostic outcome from the subsequent clinical evaluation. Another observation has been the amount of clinically relevant behavior revealed through careful human behavior observation that the interviewing physician did not observe during the actual interview.

Conclusion

Artificial intelligence could represent an untapped potential for improving sensitivity and accuracy in diagnostic procedures to detect early neurocognitive disorders.
Network Failure Quotient (NFQ) performance in ADNI‐2 and ADNI‐3: Robustness across scanner and protocol changes
Authors: Gunter Jeffrey L. , Weigand Stephen D. , Wiste Heather J. , Therneau Terry M. , Botha Hugo , Jack Clifford R. , Jones David T. ,   the Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

Background

The Network Failure Quotient (NFQ) metric summarizes functional MRI network integrity. We wanted to investigate the stability of the NFQ results across time, hardware, software and protocol changes during the last decade in ADNI Resting State (RS‐) fMRI.

Method

In ADNI‐2 (2009‐2016) RS‐fMRI was acquired on Philips scanners. In ADNI‐3 (2017‐present) RS‐fMRI is acquired on GE, Philips, and Siemens systems with “Basic” and “Advanced” variants based on the availability of simultaneous multi‐slice (SMS, multi‐band) imaging. (Table 1.) Resting state images were preprocessed by performing slice timing correction, trimming volumes from the first 10 seconds of acquired data, despiking and within‐series alignment. Simultaneous bandpass and regression was performed using spatial registration parameters and their first temporal derivatives, mean WM signal, mean CSF signal and global signal. Dual regression via GIFT was applied creating regional time courses. The NFQ is calculated as NFQ=(pDMN_to_vDMN + pDMN_to_adDMN) / (pDMN +vDMN) where pDMN_to_vDMN and pDMN_to_adDMN are correlations between time courses in the posterior DMN, ventral DMN and anterior‐dorsal DMN. pDMN and vDMN are the within‐region correlations. NFQ values from 1447 scans of 739 individual study participants (Table 1) were analyzed using linear mixed effects models to account for age, clinical diagnosis, vendor, and time trends.

Result

Box plots of NFQ values by diagnosis within ADNI‐phase and protocol are shown in Figure 2 and suggest important differences among clinical diagnoses and between ADNI‐2 and ADNI‐3. The mixed model analysis indicates that a 10‐year increase in age is associated with a 0.05±0.01 (mean±SD) increase in NFQ; individuals with MCI average roughly 0.05±0.01 higher than unimpaired and individuals with dementia average 0.14±0.02 higher. Differences by vendor for ADNI‐2 and ADNI‐3 are summarized in Figures 2 and 3 with effect sizes on par with these clinical factors. Mean NFQ for Phillips ADNI‐2 were highest (0.54±0.02); somewhat lower were Philips ADNI‐3 (0.51±0.02) and Siemens ADNI‐3 advanced (0.49±0.03); Siemens ADNI‐3 basic (0.40±0.02) and GE ADNI‐3 were the lowest (0.38±0.02).

Conclusion

NFQ values consistently increase with impairment. Vendor‐specific differences are observed and vendor changes over the life of a study introduce variability on the scale of disease‐related changes in NFQ.
Mixed brain pathologies account for most dementia in the UK’s Brains for Dementia Research cohort
Authors: McAleese Kirsty E. , Colloby Sean J. , Attems Johannes , Thomas Alan J. , Francis Paul T.
Published: December 2020

Background

Using the UK's Brains for Dementia Research (BDR) program, we investigated the frequency of neuropathological dementia diagnosis, the proportion of pure, mixed or concomitant pathologies and the pathological substrates for cognitive impairment.

Method

All cases (n = 673) underwent standardised neuropathological assessment outlined in [1]. Cases were classed as ‘pure’, ‘mixed’ or ‘concomitant’. 473 cases had clinical dementia rating (CDR) scores: binary linear regression was employed to estimate the odds of increasing CDR score due to the presence of pathologies and multiple pathologies.

Result

142 cases (21.1%) were diagnosed as controls and 531 fulfilled the criteria for a neurodegenerative disease: Alzheimer’s disease (n = 221) > Lewy body disease (n = 65) > vascular dementia (n = 50). Only 23.5% were classified as ‘pure’, 63.1% as ‘concomitant’ and 13.4% as ‘mixed’. 147 (28.9%) had no cognitive impairment and 301 had dementia. Higher burdens of hyperphosphorylated‐ τ (Hpτ), amyloid‐β and α‐synuclein burden had a three‐fold increase on the risk of being demented (OR = <3.4; 95% CI 2.1, 5.5). Regarding the conversion from mild cognitive impairment to dementia, Hpτ had a two‐fold increase on risk (OR = 1.75; 95% CI 1.16, 2.6) and the presence of multiple pathologies had a nine‐fold increase on risk (OR = 8.8; 95% CI 3.19, 24.3).

Conclusion

The majority of the BDR cohort contains multiple pathologies. Increasing burden of Hpτ and multiple pathologies greatly increases the odds of dementia. (1) Francis et al, (2018) DOI 10.3233/JAD‐180699.
Implementation of Global Action Plan on the Public Health Response to Dementia (GAPD) in Sub‐Saharan Africa: Comprehensive reviews
Authors: Ddumba Isaac
Published: December 2020

Background

Despite the fact that, age is a strongest know risk factor for onset of dementia, and developing countries are projected to have highest number of ageing population, few national dementia strategies have been put in place to address this impending scourge. In 2017, World Health Organization(WHO) released and called for countries to adapt and contextualize the Global Action Plan on the Public health response to dementia, few Sub‐Saharan countries have slowly adopted plan. The outcome of the unprecedented increase populations with dementia will be immense. The substantial increase in morbidity and mortality pose a threat to the over stretched health care system and undermine the potential to achieve sustainable development goal (SDGs).

Methods

This paper is a view of published and grey literature relevant to Global Action Plan On the Public Health Response to Dementia (GAPD) in sub‐Saharan Africa. The overall approach to the review had an exploratory and inductive focus. Articles were categorized around a guiding conceptual framework. Like; A description of structural arrangements and content of national dementia strategy development and normative underpinnings within policy frameworks

Results

Nearly all countries within the SSA hadn’t developed the national dementia strategy plans. Countries like South African, Ghana, Kenya and Ethiopia had drafts of national dementia strategy, though not yet operationalized. Few countries highlighted some of the parallel targets of GAPD within their national mental health policy and strategy, but it was not comprehensive. Countries where Civil societies that advocate/champion dementia activities were strongly presently were more likely to possess a draft of GAPD.

Conclusion

Although there some initiatives for different countries to develop national strategy for dementia plans, there are gaps in the extent of engagement of different stakeholders and how these strategies will be operationalized may limit the impact on addressing the escalating burden of dementia in Sub‐Saharan Africa. Key words: Dementia, Sub‐Sarahan Africa, national plans, GAPD.
Use of the NIH Toolbox for assessment of mild cognitive impairment and Alzheimer's disease in general population, African‐American and Spanish‐speaking samples of older adults
Authors: Gershon Richard , Nowinski Cindy , Peipert John Devin , Bedjeti Katy , Ustsinovich Vitali , Hook Julie , Fox Rina , Weintraub Sandra
Published: December 2020

Background

The world population is rapidly aging, and the prevalence of dementia due to Alzheimer’s disease (AD) and related disorders is correspondingly increasing. Thus, detecting cognitive decline in older individuals is an urgent public health concern. There is a need for brief, practical, standardized measures that are sensitive to cognitive decline and can be broadly deployed in diverse settings. Advancing Reliable Measurement in Alzheimer's Disease and Cognitive Aging (ARMADA) aims to meet this need by validating the NIH Toolbox for Assessment of Neurological and Behavioral Function® (NIHTB®) in individuals ages 65 to 85 who are cognitively healthy or diagnosed with either mild cognitive impairment (MCI) or dementia of the Alzheimer type (AD). A broad range of clinical and healthy samples have been recruited to date, including an African American sample and a Spanish‐speaking Hispanic sample to reflect the diversity of people affected by cognitive decline and to enable validation of the Spanish NIHTB. We will present baseline NIHTB results for each sample.

Method

Individuals age 65 or older who are either cognitively normal or diagnosed with cognitive impairment (MCI or early AD) have been recruited from nine clinical centers with established research cohorts. Participants complete the NIHTB and gold standard neuropsychological assessment at baseline. AD biomarkers, including PET beta amyloid level, CSF tau, and APoE genotype, are also available.

Result

As of January 2020, 656 participants have completed the baseline assessment. Early results indicate the NIHTB Cognition battery, as well as individual measures, successfully discriminates among MCI, AD and healthy controls in the general population sample (N=259). Baseline data collection for the African American and Hispanic samples will be largely complete by June 2020, and initial results will be presented.

Conclusion

Initial baseline results from the ARMADA study provide evidence that the NIHTB discriminates among older individuals with normal cognition, MCI, and early AD. Two annual longitudinal follow‐ups will evaluate how well NIH Toolbox measures predict future cognitive decline, their sensitivity to change and their association with AD biomarkers.
Semantic and logopenic primary progressive aphasia differ in pitch variation during a motor speech task
Authors: Pressman Peter S. , Lemieux Eric , Matthewson Gordon , O'Neill Chris , Ross Elliott D.
Published: December 2020

Background

Semantic variant primary progressive aphasia (svPPA) is an uncommon neurodegenerative disease associated with selective atrophy of the dominant temporal lobe. Previous observations of left hemisphere damage suggest that prosodic expression (mediated predominantly by the right hemisphere and dorsal processing streams) is often preserved and may even be enhanced as a release phenomenon in some aphasic syndromes. We predicted left temporal injury would be associated with increased pitch variation, thereby distinguishing it from other PPA syndromes such as the logopenic variant of primary progressive aphasia (lvPPA).

Method

8 patients with svPPA and 10 patients with lvPPA repeated the syllable "Pa" as part of a motor speech evaluation. We compared the coefficient of variation of fundamental frequency, perceived as vocal pitch, using a separate variances two‐way t‐test. To better understand what may drive differences in pitch variation, we also correlated pitch variation with disinhibition measures on the Neuropsychiatric Symptoms Inventory Questionnaire (NPI‐Q) and the Frontal Assessment Battery (FAB).

Result

Compared to 10 patients with lvPPA (M 4.5, SD 1.6), patients with svPPA (M 14.0, SD 10.3) displayed more variation of fundamental frequency (T = 2.6, p = 0.02). There was no correlation with either the NPIQ or FAB disinhibition measures.

Conclusion

Pitch variation during simple motor speech tasks may serve as an additional diagnostic feature to distinguish between subtypes of PPA. The temporal atrophy associated with svPPA may release hyperprosodic performances on a simple motor speech task, through a mechanism beyond behavioral disinhibition as assessed in either the NPI‐Q or the FAB. Further research is needed to better understand the neural underpinnings of prosodic differences between PPA subtypes.
What predicts who becomes a study partner in an AD cohort study?
Authors: Stites Shana D , Largent Emily A , Gill Jeanine , Harkins Kristin , Karlawish Jason
Published: December 2020

Background

Studies of persons with Alzheimer’s disease (AD) and related dementias typically include “study partners” (SPs) who report on participants’ wellbeing and function. But little is known about what factors predict the type of person who steps into the role. Knowing this will inform barriers to recruitment into AD research. It may also offer a model to anticipate who will be a caregiver in early diagnosis and treatment of AD.

Methods

We analyzed data from the Health and Retirement Study’s (HRS) Aging, Demographics and Memory Study (ADAMS). ADAMS enrolled a subset of individuals in HRS and, for each of these subjects, a SP. HRS data were collected one year prior to the first ADAMS interview and provided a detailed family record of all living, legal and biologic, relatives and a spouse’s rating of their own health. ADAMS data provided who served as a SP reporting on subject instrumental and basic activities of daily living (IADL/BADL). Three distinct regression models examined how psychosocial factors predicted each of the three SP types: spouse, adult child, and other.

Results

Among subjects with spouses, multivariable analyses showed subject’s age and having a sister predicted that a spouse was less likely to serve as SP (both p<0.05). Among subjects with children, being a women, being older, having more children, more impairments in IADLS, and not having a spouse predicted that an adult child was more likely to serve as SP (all p<0.05). Having a spouse, more children, and having more years of education predicted that a non‐spousal and non‐child person was more likely to serve as SP while being a woman and having a daughter were associated with a lower probability that a non‐spouse and non‐child served as SP (all P<0.05).

Conclusions

Different factors predict the type of person who may serve as a SP. Our findings show patterns in interpersonal relatedness, educational attainment, and gender norms that may underlie differences in decisions about who serves as SP. This information may help inform recruitment and retention in AD research.
The status of current clinical practice in diagnosis of young onset dementia in England: Findings from The Angela Project
Authors: Carter Janet , O'Malley Mary , Campbell Jackie , Stamou Vasileios , La Fontaine Jenny H. , Oyebode Jan , Parkes Jacqueline
Published: December 2020

Background

The presentation of dementia in young people is complex and challenging, often resulting in delays in receiving a confirmed diagnosis and appropriate support. A recent Delphi consensus has derived minimum and gold standards for the diagnostic workup that international expert clinicians consider best practice. This presentation will review the results of a large case note audit that assessed compliance with these standards in current UK clinical practice.

Method

403 patient records of young people who received a diagnosis of dementia in the last 5 years were audited according to our minimum and gold standards. Records were obtained from memory services within eight different National Health Service locations from across England.

Result

We found significant differences between the sites in meeting the standards, though all sites had median scores that were below 50% compliance for both the minimum and gold standard. This suggests that current UK assessments fail to reach an acceptable standard.

Conclusion

Further consultation with clinicians and young people with dementia is necessary to understand local impediments to meeting an acceptable standard and to identify interventions that can lead to improvement.
Association between integrated cognitive assessment (ICA) and measures of brain structure in mild cognitive impairment and mild Alzheimer’s disease
Authors: Khanbagi Mahdiyeh , Marefat Haniye , Karimi Hamed , Kalafatis Chris , Vahabi Zahra , Razavi Seyed‐Mahdi Khaligh
Published: December 2020

Background

Integrated Cognitive Assessment (ICA) is an artificial intelligence‐assisted test for cognitive assessment in mild cognitive impairment (MCI) and Alzheimer’s Disease (AD) (Khaligh‐Razavi et al., 2019). ICA is shown to be accurate in detection of subtle cognitive impairments in MCI/ AD, and have demonstrated a strong association with the level of neural damage, as measured by NfL. However, the link between ICA and measurements of brain atrophy has not been studied yet. Here, we investigated the link between participant’s performance in ICA test and their cortical volume and thickness; we were further interested to see whether the impairment detected by ICA precedes that of brain atrophy.

Method

High‐resolution (1mm3) MRI scans were acquired from 45 participants (age= 64.63±7.46): 15 MCI patients, 10 mild AD, and 20 healthy controls (HC). All the participants took ICA. Structural images of the brain were then reconstructed using FreeSurfer software for volumetric and cortical thickness measurements.

Result

ICA shows significant correlations with cortical thickness in various brain regions, such as part of the lingual and parahippocampal cortex (r= 0.7, p<10‐11), lateral occipital (r= 0.48, p<10‐6), inferior temporal (r= 0.43, p<10‐5) and fusiform (r=0.4, p<10‐4) in the left hemisphere. Within the right hemisphere, ICA has a significant correlation with precuneus (r= 0.45, p<10‐5) and lateral occipital (r=0.5, p<10‐7). ICA has a large effect size (Cohen’s d= 0.95, p<0.001) in differentiating HC from MCI and HC from mild AD (Cohen’s d= 1.98, p<0.0001). Cortical thickness and left hippocampal volume could differentiate HC from mild AD (Cohen’s d= 0.88, p<0.05; and d= 0.8, p<0.05 respectively), but not HC from MCI.

Conclusion

We found a significant association between participants’ ICA score and the thickness of the cortex in some of the key brain areas, including parahippocampal, that are anatomically identified among the early areas affected by tau‐pathology (Braak and Braak, 1991). Furthermore, participant’s ICA score could better differentiate HC from MCI or mild AD compared to their hippocampal volume, suggesting that impairment in ICA performance precedes that of hippocampal volume.
Estimating an individual's placement on a theoretical continuum using longitudinal cognitive trajectories: Relationships with longitudinal amyloid and Tau‐PET
Authors: Properzi Michael J. , Buckley Rachel F. , Papp Kathryn V. , Farrell Michelle E. , Jacobs Heidi I.L. , Hanseeuw Bernard J. , Rabin Jennifer S. , Chhatwal Jasmeer P. , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. , Schultz Aaron P.
Published: December 2020

Background

Theoretical models of the Alzheimer’s disease (AD) continuum posit a curvilinear trajectory of declining cognition, with accumulating AD pathology catalyzing an accelerated rate of decline. Assuming this continuum can be modelled, individuals can be placed along the curve based on their longitudinal cognitive performance. In this way, we can reduce multi‐dimensional data to a single parameter (simplification/parsimony) and remove non‐linearity in the cognitive data.

Method

317 participants from the Harvard Aging Brain Study (72 years (7.6); Female:61.5%) underwent longitudinal neuropsychological assessments (follow‐up: 5.9years (2.1) range:1.7‐9.1) and PIB‐PET imaging. A subset of participants (n=230) also underwent FTP‐PET imaging. Cognition was measured using the Preclinical Alzheimer Cognitive Composite (PACC). Using iterative non‐linear least squares optimization, we defined a curvilinear function (incorporating linear, quadratic and exponential components) that best described the group level PACC trajectory of all participants (Figure 1). Each subject’s longitudinal PACC trajectory was then located on the resulting curve using trust‐region‐reflective non‐linear least squares optimization, solving for an individual’s time offset (toffset). We examined associations between toffset, age, sex, apoe4 status, cross‐sectional PIB‐PET and FTP‐PET. We also examined toffset in relation to changing PIB‐PET and FTP‐PET.

Result

Individuals with a more advanced toffset had higher levels of entorhinal (EC) and inferior temporal (IT) FTP‐PET (r=0.42, p=<<0.001; Figure 2A&B.), and also showed higher PiB‐PET signal (r=0.36, p=<<0.001; Figure 2C.) PIB accumulation appears earlier in toffset followed by EC TAU and finally IT TAU, suggesting that a biomarker cascade is being captured by toffset (Figure 3). FTP‐PET and PIB‐PET did not interact to predict toffset. There was no effect of age or APOE4, or an interaction between the two, on toffset.

Conclusion

Using toffset, estimating an individual’s position along a hypothetical clinical continuum can inform the unique contributions of AD biomarkers, and test hypotheses about temporal sequences of events. This data‐reduction approach is superior to that of pulling cognitive slopes, as the tpffest removes complex non‐linearities inherent in the data (Figure 4). We also illustrate that an interaction between FTP‐PET and PIB‐PET does not predict toffset, suggesting a common upstream mechanism that may underlie both Aβ and tau to drive decline, at least during the preclinical stages of disease.
Generation of mid‐region murine monoclonal antibodies against multiple structural isoforms of amyloid‐beta by hybridoma technology
Authors: Stockmann Julia , Beyer Léon , Galkowski Sandy , Woitzik Nathalie , Güldenhaupt Jörn , Gerwert Klaus Bernhard
Published: December 2020

Background

The immuno‐infrared‐sensor enables the diagnosis of Alzheimer’s disease by measuring the secondary structure distribution of Amyloid‐beta (Aß) in CSF and blood plasma. For this technique an antibody is essential, which binds to all conformations of the biomarker peptide. We developed different immunization strategies to generate monoclonal Aß‐antibodies (mAb) using wt and APP Knock‐Out (KO) mice.

Method

KO and wt mice were immunized with different Aß peptides. With an antigen‐specific ELISA antibody‐producing hybridoma cells were screened and selected for performance tests with the immuno‐infrared sensor. Immuno‐infrared‐analyses provided a detailed characterization of the structural selectivity of the antibodies.

Result

Both KO and wt mice generated multiple Aß specific antibodies, though KO mice yielded 8 times more Aß‐positive antibodies than wt. All antibodies, probably polyclonal, revealed binding to alpha‐helical or disordered monomeric Aß as well as to ß‐sheet enriched Aß (oligomers, fibrils). Additionally, seven of these antibodies differentiated between AD patients and healthy controls in cerebrospinal fluid (CSF) samples.

Conclusion

With our immunization strategy we were able to generate multiple antibodies for the diagnosis of Alzheimer’s disease with the immuno‐infrared sensor. We generated seven antibodies, which enable the differentiation of AD patients and healthy controls by analyses on CSF. References: [1] Nabers, A., Ollesch J. et al. (2016) J. Biophotonics, 9. 224‐234. [2] Nabers, A. et al. (2018) EMBO Mol. Med. 10, e8763. [3] Nabers, A et al. (2019) Alzheimer’s Dement. Diagnosis, assess. Dis. Monit., 11, 257‐263. [4] Stocker, H et al. (2019), Alzheimer's & Dementia, in press.