bluuebunny/crossref_metadata_2025 huggingface dataset:
Late‐life literacy training for improving memory and brain connectivity: Baseline results
Authors: Resende Elisa de Paula França , Lara Vivian Proença , Santiago Ana Luisa Carvalho , Friedlaender Clarisse Vasconcelos , Rosen Howard J , Grinberg Lea Tenenholz , Silva Lênio Lúcio Gávio , de Souza Leonardo Cruz , Caramelli Paulo
Published: December 2020

Background

Higher education acquired through the lifespan is believed to buffer the cognitive decline associated with neurodegenerative diseases. However, whether acquiring education later in life can improve memory is unknown.

Methods

We recruited illiterate adults that enroll in a late‐life literacy program to determine the impact of literacy training in adulthood on memory. Participants underwent baseline literacy tests and episodic memory was assessed with the Free and Cued Selective Reminding test (with pictures).

Results

At baseline, 43 illiterate adults that did not know how to read and write participated in the study. They had a mean age of 50.3 (SD 14.3) year‐old, 19 (44%) were males, 37 (90%) were non‐Caucasians and 24 (57%) were from low‐socioeconomic background. The main reason they did not attended school when they were young was that they had to work (n=21, 49%). Baseline clinical characteristics of participants were smoking in 26%, depression in 25% and anxiety in 16%. The mean free delayed‐recall was 10.6 (SD 3.1), out of 16 figures.

Conclusion

Here we present the baseline characteristics of this group of illiterate adults that engage in a late‐life literacy program. The results show that the participants recruitment is feasible and representative of such illiterate adult populations. Although episodic memory is normal, there is room for memory improvement to be studied in the follow up visit.
Knockout of microglial P38A mapk in a mouse model of Alzheimer’s disease
Authors: Braun David J. , Davis Verda A. , Van Eldik Linda J.
Published: December 2020

Background

The p38a MAPK signaling pathway is a well‐established regulator of neuroinflammation, and pharmacological inhibitors of this pathway can protect against cognitive impairment in animal models of Alzheimer’s disease (AD). This protection by p38a inhibitors might be mediated via protective effects on neurons, anti‐inflammatory effects on glia, or some combination thereof. To assess whether reduction of p38‐dependent microglial proinflammatory responses is beneficial in this context, we generated AD model mice with microglial knockout (KO) of p38a.

Method

The APPswe/PS1dE9 (MMRRC #34832) mouse AD model was crossed with p38afl/fl mice (Jax #031129) to generate AD model mice homozygous for the floxed p38a allele. These were subsequently crossed with CX3CR1CreERT2 mice (Jax #020940) that express a tamoxifen‐inducible promoter allowing for removal of p38a from microglia. This breeding scheme generated four groups of mice, used in a 2 x 2 study design: WT and AD mice with floxed p38a, with or without a copy of the myeloid‐specific Cre allele. All mice were placed on tamoxifen diet (400 ppm) for 4 weeks beginning at 5 months of age, near the beginning of amyloid plaque deposition in this AD model. After administration of tamoxifen, mice were returned to normal chow for several months, allowing turnover of peripheral myeloid cells. Mice underwent behavioral testing in open field and novel spatial recognition y‐maze (8 months of age), and radial arm water maze (11 months of age). Microglial isolation via fluorescence‐activated cellular sorting and subsequent RNAseq analysis was performed on a subset of 4 mice per group.

Results

Microglial p38a KO had no effect on the hyperlocomotive phenotype associated with amyloid overexpression in this model; however, p38a KO increased errors in the RAWM test of spatial learning and memory in the AD model but not WT mice.

Conclusions

The p38a signaling pathway in microglia is important in restricting amyloid‐associated cognitive decline. We are currently characterizing the effects of microglial p38 KO on amyloid pathology, neuroinflammation, and microglial gene expression.
Cataract surgery is associated with reduced risk for Alzheimer’s disease
Authors: Lee Cecilia S , Gibbons Laura E , Lee Michael L , Lee Aaron Y , Yanagihara Ryan T , Crane Paul K , Larson Eric B
Published: December 2020

Background

Visual improvement after cataract surgery is well‐established, but the literature on the potential impact of cataract surgery on Alzheimer’s disease (AD) is conflicting. Using data from a large, well‐characterized cohort, we sought to determine whether cataract surgery was associated with lower risk of developing AD.

Method

The Adult Changes in Thought (ACT) study is a 25‐year‐old ongoing population‐based study of participants recruited from Kaiser Permanente Washington (KPW) membership rolls, aged ≥ 65 without dementia at enrollment and followed until dementia or death. AD was diagnosed using established research criteria. Extensive clinical data were obtained during study visits and via KPW electronic medical records (EMR). Eye‐related diagnoses and procedures were based on ICD‐9/10 and CPT codes. We used Cox proportional hazard regression modeling for probable or possible AD. Because healthier participants might have been more likely to receive surgery, we built marginal structural models accounting for several health and cognitive factors as one of several secondary analyses. We also examined the associations between AD and glaucoma surgery as a comparator procedure.

Result

A total of 3,719 participants with cataract diagnosis were included, with 840 incident AD cases. 1,815 (49%) underwent cataract surgery and 1,914 did not (Table 1). The adjusted HR of developing AD in people who underwent cataract surgery was 22% lower than those who did not undergo cataract surgery (HR=0.78, [95%CI 0.68, 0.91], p=0.001), and the effect was stronger for recent surgery (Table 2; Figure). Secondary analyses to account for healthy patient bias yielded similar results, as did omitting the original cohort with a shorter EMR history, or just considering cataract diagnosis after baseline. Ignoring cataract surgery 2 years prior to AD yielded stronger effect. Glaucoma surgery was not associated with AD.

Conclusion

Cataract surgery is associated with lower risk of AD in this prospective, population‐based study. This finding does not appear to be due to healthier participants receiving surgery. Further research on the implications of eye conditions and treatments on Alzheimer’s disease is warranted.
Characterization of older, cognitively normal obstructive sleep apnea patients at risk of prospective cognitive decline using the NIA‐AA Research Framework
Authors: Bubu Omonigho M. , Turner Arlener D. , Jean‐Louis Girardin A , Osorio Ricardo S.
Published: December 2020

Background

The association between Obstructive Sleep Apnea (OSA) and cognition in older‐adults is conflicting. We determined to characterize older OSA‐patients using the NIA‐AA Research Framework and test whether OSA accelerates cognitive decline in preclinical Alzheimer’s disease (AD)

Method

Community‐dwelling cognitively normal elderly participating on a study on memory, sleep and aging, with baseline AD biomarker data and both baseline and follow‐up neuropsychological data were included. OSA was defined using AHI4%. Data‐driven, clinically relevant thresholds for CSF‐Aβ42 (≤375pg/ml), and CSF P‐tau (≥53.7pg/ml) indicated OSA participants AT(N) status using the NIA‐AA Research Framework. Twenty‐four participants with non‐AD pathologic change defined as A‐T+ were excluded leaving 127 for the analysis. Main outcome was the annual rate‐of‐change in global cognition (calculated as an average composite Z‐score of episodic memory, language and executive function cognitive tests domains). Linear mixed‐effects models with random intercept and slope were used to assess associations between AT(N) characterized OSA subjects, and longitudinal changes in global cognition, controlling for age‐at‐baseline, sex, APOE4‐status, years‐of‐education, and their interactions with time.

Result

Of the 127 participants, 81 (63.8%) were women. The mean (SD) age was 69.6 (7.3) years and follow‐up time was 2.46 (0.64) years. Eight (6.3%) met biomarker criteria for AD (OSA+/A+/T+ [n=4] and OSA‐/A+/T+ [n=4]). Forty‐four participants (34.6%) were amyloid positive (OSA+/A+ [n=20] and OSA‐/A+ [n=24]). Sixteen (12.6%) were OSA+/A+/T‐, and 20 (15.7%) were OSA‐/A+/T‐. Eighty‐three (63.4%) had normal AD biomarkers (OSA+/A‐/T‐ [n=40] and OSA‐/A‐/T‐ [N=43]). Regardless of OSA status, relative to normal AD biomarkers, amyloid positive participants i.e. AD pathologic change, showed significant faster rate‐of‐decline in global cognition (β = −0.066, 95%CI, −0.088, −0.046; P < .001). However, OSA+/A+/T‐ participants showed even more significantly faster rate‐of‐decline in global cognition compared to OSA‐/A+/T‐ participants (β = −0.042, 95%CI, −0.063, −0.019; P < .001), suggesting an OSA/Aβ42 synergism independent of PTau. OSA+/A‐/T‐ or OSA‐/A‐/T‐ participants (normal AD biomarkers) did not show any significant cognitive change over time.

Conclusion

Among amyloid positive healthy‐elderly, OSA and Aβ demonstrate synergism related to cognitive decline that might be independent of tau deposition. Clinical trials in a population of elderly OSA cognitive‐normal individuals should target at minimum persons with Alzheimer’s pathologic change.
Functional assessment of cognitively impaired older adults: Are we asking the right questions?
Authors: Calia Clara , Pickett Eleanor , O'Donal Freddie , Parra Mario A.
Published: December 2020

Background

Recent attention has turned to the development of preventative treatments for Alzheimer’s disease (AD) by targeting the early stages of impairment. However, current neuropsychological and functional assessments are not ideally suited to identify early deviations from healthy ageing (HA). The Details of Functions of Everyday Life (DoFEL; Parra & Kaplan, 2019) is a theory‐driven scale that incorporates cognitive constructs sensitive to the preclinical stages of dementia (memory binding). DoFEL can help assess the extent to which instrumental functions of daily living are supported by such cognitive abilities and if so, whether by asking the right questions through such a scale we could unveil subtle and still undetected impairments. We predict this would increase the sensitivity of scales to detect older adults with cognitive impairment who are at a high risk of dementia.

Methods

Twenty‐five MCI and 21 HA controls (ACE‐R score ≥ 88) (Mioshi et al., 2006) underwent an extensive baseline neuropsychological assessment followed by yearly follow‐up assessments. The DoFEL is an informant‐based neuropsychological assessment that measures a range of functional abilities which rely on different forms of binding functions. This measure includes 82 statements subdivided into 7 functional domains that comprehensively assess different aspects of daily living. Higher DoFEL score indicate greater impairment.

Results

Five key findings from this study were: (1) The total DoFEL score differentiates MCI from HA U=406.00, p=0.002. Higher scores were detected in individuals with MCI (Mdn= 0.41, Mean rank= 29.24) than in the HA (Mdn= 0.35, Mean rank= 16.67). (2) Individuals with MCI showed domain‐specific impairments on DoFEL such as Objects and People, Technology and Communication, Work and Social Life. (3) Relative to HA, MCI patients presented with impaired functional abilities that rely on relational (i.e., forming associations, p=0.001) and conjunctive (i.e., forming object identity, p=0.004). (4) DoFEL scores correlate with (r= ‐0.62, p=0.000), and predicts cognitive performance on the ACE‐R (β= ‐128.68, t(44)= ‐6.97, p=0.000).

Conclusion

DoFEL can detect differences between individuals with MCI and HA in overall and specific functional abilities seemingly supported by binding functions and therefore may be a useful tool to identify individuals at risk of developing AD.
Sensitivity of objective and subjective sleep features to tau and Aβ burden in healthy older adults
Authors: Winer Joseph R. , Morehouse Allison , Fenton Laura E. , Harrison Theresa M. , Baker Suzanne L. , Jagust William J. , Walker Matthew P.
Published: December 2020

Background

Impaired sleep is a risk factor for Alzheimer’s disease (AD) as well as a symptom of AD pathological progression. Recent work has established associations between disrupted sleep electrophysiology and AD pathology before the onset of AD symptoms. However, it is not understood how real‐life sleep features, both objective and subjective, are associated with tau and Aβ burden in the context of early AD.

Method

We compared objective and self‐reported measures of sleep quantity and quality to 18F‐FTP tau PET and 11C‐PIB Aβ PET in healthy older adults (N=80, age 78.9 ± 6.9, 65% female). Objective sleep was assessed using 7 nights of at‐home wristwatch actigraphy, with analyses focusing on sleep duration, efficiency, fragmentation and timing (midpoint). Subjective sleep was assessed using the Pittsburgh Sleep Quality Index. 18F‐FTP SUVRs (80‐100 min, inferior cerebellar gray reference) were calculated for each subject in a composite ROI of temporal cortical regions. A global cortical 11C‐PIB DVR (0‐90 min, cerebellar gray reference) was also calculated.

Result

Shorter average sleep duration was associated with significantly greater cortical Aβ (Figure 1A; r=‐.23, p=0.04). In contrast, worse sleep efficiency, rather than duration, was associated with greater tau burden (Figure 1B; r=‐.24, p=.03). Of clinical interest, neither self‐reported sleep duration or efficiency were associated with tau and Aβ burden. Indeed, greater tau and Aβ burden were associated with worse accuracy in self‐reported estimation of sleep, relative to objective amount (Figure 2; r=0.23, p=0.04).

Conclusion

These findings suggest that specific actigraphy‐based measures of sleep, assessed in the ecological at‐home setting, are differentially predictive of tau and Aβ burden. This dissociation may reflect distinct effects of these anatomically segregated pathologies in early stages of AD and their respective impact on different aspects of sleep‐regulating brain networks. Of translational relevance, participants’ own subjective sleep estimates did not predict tau or Aβ burden, suggesting that objective sleep assessments may be more clinically appropriate, reflecting real‐life behavior patterns in the context of aging. Finally, the severity of both tau and Aβ burden predicted the degree of inaccuracy in participants’ assessment of their own sleep duration, the underlying neural mechanisms of which remain unclear.
Impact of intrathecal cell therapy with autologous stromal cells on short‐term memory binding in early Alzheimer’s disease: One‐year follow‐up assessment
Authors: Guinea Sara Fernández , Zurita Mercedes , Mucientes Jorge , García Estefanía , Marqués Javier González , Parra Mario A. , Vaquero Jesús
Published: December 2020

Background

We had previously reported that the administration of autologous stromal cells (ASCs) therapy to two patients with mild AD dementia led to a global increase in cerebral glucose metabolism which was accompanied by significant improvement of visual short‐term memory binding (VSTMB), a function known to be a marker of AD. We suggested that intrathecal administration of autologous ASCs could be considered a new therapeutic strategy for AD dementia (Vaquero et al., 2019). We were interested in investigating the post‐intervention durability of such cognitive improvements.

Methods

We studied two AD patients with cerebral beta‐amyloid neuritic plaques detected with 18FFDG‐PET. The patients received every three months 100 million of ASCs by intrathecal route, until a total dose of 300 million. None received any other medication for its disease at the time of receiving cell therapy. Clinical and neuroimaging studies were performed previous and after the therapy, including brain glucose metabolism by 18F‐FDG‐PET and assessment with the visual short‐term memory binding task (VSTMBT). This task has been proposed as a preclinical marker of AD. It requires subjects to detect whether or not two combinations of shape and colour change across two sequential arrays. Here we report on the assessment of these patients one year after the therapy. We compared them with 4 AD patients who did no undergo stem cell therapy.

Results

Single case statistics revealed that benefits drawn by treated patients from the therapy remained a year after. Using a more taxing version of the VSTMB test (memory load of 3 items) we observed that, after the therapy, the chance that an untreated AD patient would show more impairment was 75.45% (p= 0.24) for Case 1 and 89.23% (p=0.11) for case 2. This chance remained after 1 year post‐treatment for Case 1 (75.45%, p=0.24) and increased for Case 2 (96.89%, p=0.031).

Conclusion

Improvements of memory functions known to be marker for AD in patients who underwent stem cell therapy remained stable after one year post‐intervention. This offers a new therapeutic strategy for AD.
Associations between age, sex, menopause and cardiometabolic risk profiles with brain structure: A latent class analysis
Authors: Than Stephanie , Moran Christopher , Beare Richard , Vincent Amanda , Srikanth Velandai K
Published: December 2020

Background

Older age and female sex are both risk factors for the development of dementia. This may be related to menopause, a midlife event associated with an increased incidence of cardiometabolic conditions for women. We aimed to identify latent groups of cardiometabolic risk, explore their interactions with age, sex and menopause, and examine the associations with imaging biomarkers of dementia.

Method

Cross‐sectional study of participants with cardiometabolic and structural brain magnetic resonance imaging data from the UK Biobank, a community‐based cohort of men and women over 40 years of age in the United Kingdom. We applied latent class analysis to age, sex, menopausal status and available cardiometabolic measures using poLCA in R. Information criteria determined the best model fit. We then used logistic regression to examine class‐dependent associations with brain volumes.

Result

Data were available for 1824 postmenopausal women, 233 premenopausal women and 2165 men (median age 63.3, range 44.6‐78.0 years). LCA identified 4 distinct classes: an “unhealthy” group of men and postmenopausal women (22.5%), a “hypertensive group” of men and postmenopausal women (10.4%), a “healthy” group of postmenopausal women (31.9%), and a younger “healthy” reference group of men and premenopausal women (35.2%). Mean total brain volume was greatest in the reference group (1517 mL ± 71.6), followed by the “healthy” postmenopausal group (1516 mL ± 70.7), the “hypertensive group” (1493 mL ± 70.8), and the “unhealthy” group (1475 mL ± 69.2).

Conclusion

Older age and menopause are associated with reduced brain volumes. Differences in cardiometabolic risk profiles appear to moderate these associations.
Protein‐protein interaction networks of genes associated with different cognitively defined subtypes of late‐onset Alzheimer's disease in five white populations identify novel candidate genes
Authors: Mukherjee Shubhabrata , Mez Jesse , Trittschuh Emily H. , Saykin Andrew J. , Gibbons Laura E. , Sanders R. Elizabeth , Fardo David W. , Crane Paul K.
Published: December 2020

Background

We previously defined late‐onset Alzheimer's disease (AD) subgroups using cognitive profiles (memory, executive functioning, language, and visuospatial ability) for individuals with Clinical Dementia Rating < 2 in five White populations. This approach results in six subgroups: those with no domain with a substantial relative impairment; those with an isolated substantial relative impairment in one of four domains, and those with multiple domains (mixed) with substantial relative impairments. We performed gene network analysis to find unique and overlapping genes to enhance our understanding of AD heterogeneity.

Method

We performed genome‐wide association studies (GWASs) for each of the AD subtypes against cognitively normal elderly adjusting for age, sex, and population substructure using PLINK v1.9 in each population and meta‐analyzed results using METAL. We excluded the AD‐Executive function group because of small sample size. For each of the subtypes, we performed gene‐wide association analyses using VEGAS v2 and combined results with human protein‐protein interaction (PPI) data using a dense module searching method to identify candidate gene modules. This approach searches the entire interactome and exhaustively evaluates the combined effects of multiple genes to identify networks of interacting genes with low p‐values for the phenotype of interest. We performed gene network analysis for AD using Stage 1 GWAS summary statistics reported in the 2019 IGAP GWAS of AD paper and compared genes in the top module for AD to the top module for each AD subtype.

Result

The top gene network module for AD and AD subtypes were enriched for genes in Chromosome 19. Ubiquitin C (UBC) was the hub gene in each of the top modules (See Figure 1). Very few genes were common across the different subtypes and with AD, and except for UBC, all of them reside in Chromosome 19 (See Figure 2).

Conclusion

Network analyses using PPI data identified novel candidate genes for cognitively‐defined AD subtypes, which supports the AD heterogeneity idea. Further functional enrichment analysis is needed to determine whether these candidate loci may provide targets for interventions to ameliorate AD.
Neurodegenerative substrate of behavioral changes in Alzheimer’s disease
Authors: Ringman John M , Pawar Sanjay , Montoya Lucy , Ge Xinting , Qiao Yuchuan , Shi Yonggang
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) are common in Alzheimer’s disease (AD) and, with advancing disease, are a major cause of disability and the principal cause of institutionalization. With the advent of tau imaging with PET, we can directly interrogate the neurodegenerative changes associated with behavioral changes in AD.

Method

We performed flortaucipir PET scans in persons carrying autosomal dominant AD (ADAD) mutations and with late‐onset AD (LOAD). The Neuropsychiatric Inventory (NPI) was administered to knowledgeable study partners and the frequency x severity scores calculated for each behavioral domain. All underwent scans with flortaucipir using 110‐minute uptake time and 30‐minute dynamic scanning. PET scans were first normalized to T1 space and then corrected for partial volume effects using Mueller‐Gaertner approach. SUVRs for PET scan were calculated using the whole cerebellum grey matter as a reference. Regional average SUVRs were finally obtained for each ROI mapped from the Desikan‐Killiany Atlas. NPI scores for each domain were correlated with SUVRs using Pearson’s correlations.

Result

We included 24 participants (53% male, mean MMSE = 21, CDR = 0.8, CDR SOB = 4.6) with ADAD mutations (mean age = 38) and 6 participants with LOAD (mean age = 60). Strong (p’s < 0.01) correlations were found for affective behaviors (apathy>depression>anxiety) and tau SUVRs in the anterior cingulate gyrus and medial orbitofrontal lobe. The highest correlations were found between apathy and tau signal in these areas (r = 0.67, p < 0.001).

Conclusion

Changes in affect correlated strongly with tau pathology in the medial and orbital frontal lobes. This is consistent with previous studies implicating a role or these areas in apathy and depression. These findings enhance our understanding of the pathology underlying affective symptoms in AD and suggest a role of tau PET in identifying those at the greatest risk for these debilitating symptoms.
Diagnosis and management of neuropsychiatric symptoms in early Alzheimer’s disease in the memory clinic setting
Authors: Eikelboom Willem S. , Coesmans Michiel , Singleton Ellen H. , Ossenkoppele Rik , van Swieten John C. , van den Berg Esther , Papma Janne M.
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) are highly prevalent in early Alzheimer’s disease (AD) and are associated with poor clinical outcomes. Although non‐pharmacological interventions are considered first‐line treatment for NPS in AD, they are rarely implemented into the memory clinic. Here, we present the protocol of our intervention study aimed to structure and standardize the detection and treatment of NPS in AD in the memory clinic, and provide preliminary data from our control group to obtain more insight in the current memory clinic care as usual (CAU) of NPS in AD.

Method

We are currently enrolling a control group that receives CAU at six memory clinics in and around Rotterdam, the Netherlands. From spring 2020 onwards, a second wave of subjects will undergo the Describe, Investigate, Create, Evaluate (DICE) method in order to standardize and structure the management of NPS in AD. Primary outcomes are the quality of life of patients and their caregivers measured by the Qol‐AD. Secondary outcomes include NPS change, caregiver burden, the experiences of the participants that underwent the DICE method, and the cost‐effectiveness of the intervention. We conducted interviews with physicians to investigate the CAU for NPS in the memory clinic.

Result

To date, 26 community‐dwelling patients have been enrolled in the control group together with their caregivers (n=19 AD dementia, n=7 mild cognitive impairment due to AD, mean [SD] Mini‐Mental State Examination = 23.5 [3.6]). Most common NPS presented at baseline were depression (80.8%), apathy (65.4%), and irritability (61.5%). Although we found heterogeneity in the CAU of NPS between participating sites, most memory clinics do not routinely screen for NPS (2/6 sites) and/or to carry out an elaborate assessment of NPS and its potential underlying causes (2/6 sites).

Conclusion

Preliminary data on the CAU indicate a high prevalence of NPS that are currently not routinely investigated nor treated in the memory clinic. Early recognition and thorough assessment of NPS seem important first steps to facilitate the use of non‐pharmacological treatments for these symptoms in AD. Our intervention study aims to facilitate an early diagnosis and adequate management of NPS in early AD in the memory clinic.
Cerebral hemodynamics using BOLD MRI in MCI
Authors: Hajjar Ihab , Henley Brandon
Published: December 2020

Background

Alterations in cerebral hemodynamics are a key factor in the onset and progression of Alzheimer’s disease (AD). In this report we describe we describe a procedure to measure multiple cerebral hemodynamic features using magnetic resonance imaging (MRI) with simultaneous multi‐dimensional physiological signals.

Methods

We assembled an MRI‐compliant system that records continuous systemic blood pressure, pulse rate, respiratory rate and end‐tidal CO2 synchronized with the MRI image acquisitions of resting state blood oxygenation level depend (BOLD) MRI. We employed the concept of Principal Dynamic Modes (PDMs) to model the effect of three determinants: mean arterial blood pressure (MABP), end‐tidal CO2 (ETCO2), and pulse rate (PR) to quantify cerebral autoregulation (CA), CO2 vasoreactivity (CVR), and pulse rate reactivity (PRR). BOLD images were acquired at rest and during an 8% 2‐minute CO2‐challenge. Data were collected as part of the baseline assessment of the participants in the Brain Stress Hypertension and Aging cohort which includes those with normal cognition and mild cognitive impairment (MCI).

Results

The hemodynamic set up was well tolerated and successful analysis of data were obtained from 129 participants ( age 65, 80 women, 60 African Americans, 79 MCI). There was a significant correlation between the PDM‐based calculation of CVR and that obtained during CO2 challenge (R2 = 5.19%, p = .016). There was also a significant correlation between PDM‐based measure of CA and the ratio of sit‐to‐stand change in MABP to PR (R2 = 6.86%, p = .005). Relative to those with normal cognition (NC), CA was reduced in MCI in the parietal lobe, CVR was reduced in MCI in the occipital and temporal lobes, and PRR was reduced in multiple lobes lobes. Reduced CVR and PRR was associated with worse cognitive scores.

Conclusions

The employed acquisition and analysis of MRI hemodynamic procedures is well‐tolerated, and identified cerebral hemodynamic alterations in MCI, related to PR and ETCO2 changes. These offer a potential for collection of hemodynamics during routine MRI in cognitive disorders.
APOE‐ε4 shapes temporo‐parietal network properties in middle‐aged, cognitively unimpaired individuals: A graph theory analysis
Authors: González‐de‐Echávarri José Maria , Cacciaglia Raffaele , Falcon Carles , Sánchez‐Benavides Gonzalo , Suárez‐Calvet Marc , Milà‐Alomà Marta , Arenaza‐Urquijo Eider M , Grau‐Rivera Oriol , Operto Greg , Vilor‐Tejedor Natalia , Sala‐Vila Aleix , Crous‐Bou Marta , Minguillón Carolina , Fauria Karine , Zetterberg Henrik , Blennow Kaj , Gispert Juan Domingo , Molinuevo Jose Luis ,   ALFA study
Published: December 2020

Background

The allele ε4 of the APOLIPOPROTEIN E gene (APOE‐ε4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). However, the underlying mechanisms are not well understood. Our objective was to assess the effect of the APOE‐ε4 allele dose on brain functional connectivity networks in cognitively unimpaired middle‐age individuals, using resting‐state functional magnetic resonance imaging (rs‐fMRI) and graph theory.

Method

This research included resting state 3 tesla functional Magnetic Resonance Imaging (rs‐fMRI) data from 349 cognitively unimpaired subjects from the ALFA+ cohort study, in which clinical, genetic and AD core cerebrospinal fluid biomarkers (Aβ42 and p‐tau), measured using Elecsys® immunoassays (Roche Diagnostics) data were also collected. The sample was composed of 127 men and 222 women with a mean age of 60.2 years, 32 homozygous ε4, 123 heterozygous ε4 and 164 non‐carriers. The CONN toolbox (matlab toolbox) was used to preprocess and analyze the fMRI images with the default pipelines and adjusting by age, sex and years of education. ROI‐to‐ROI bivariate correlations were performed using cortical ROIs of Harvard‐Oxford atlas to compute each subject adjacency matrix. After thresholding and binarizing these results, graph theory was used to analyze the differences between APOE‐ε4 groups and false discovery rate (p‐FDR= 0.05) was applied.

Results

We observed APOE‐ε4 allele‐dose dependent effects on multiple network properties, including reduced degree centrality, reduced global efficiency and increased average path length located in temporo‐parietal nodes: left temporo‐occipital fusiform cortex, occipital fusiform gyrus, right lateral parietal cortex, temporal pole and posterior superior temporal gyrus. In addition, increased betweenness centrality of the precuneus was also observed. (Figure 1). These results survived after adjusting the model for Aβ42 and p‐tau values.

Conclusion

APOE‐ε4 allele modulates the functional integration among cortical nodes within temporo‐parietal networks, which typically present structural and metabolic alterations in AD. Importantly, these effects survived after adjustment by AD core biomarkers, suggesting that they were selectively mediated by APOE genotype. The inclusion of neuropsychological data shall clarify whether this distinctive network configuration may represent a network vulnerability or underlie compensatory strategies.
Neuroinflammatory processes, A1 astrocyte activation and protein aggregation in the retina of Alzheimer’s and Parkinson's disease patients: Possible biomarkers for early diagnosis
Authors: Angelantonio Silvia Di , Pizzarelli Rocco , Pediconi Natalia , Rosito Maria , Greco Federica Lo , Grimaldi Alfonso , Giubettini Maria
Published: December 2020

Background

Alzheimer’s disease (AD), a primary cause of dementia in the aging population, is characterized by extracellular amyloid‐beta peptides aggregation, intracellular deposits of hyperphosphorylated tau, neurodegeneration and glial activation in the brain. It is commonly thought that the lack of early diagnostic criteria is among the main causes of pharmacological therapy and clinical trials failure therefore, the actual challenge is to define new biomarkers and non‐invasive technologies to measure neuropathological changes in vivo at pre‐symptomatic stages. Recent evidences obtained from human samples and mouse models indicate the possibility to detect protein aggregates and other pathological features in the retina, paving the road for non‐invasive rapid detection of AD biomarkers.

Method

Human retinal slices from AD (n=20) and PD (n = 10) patients and age matched controls (n=20/10) were purchased from Human Eye Biobank for Research, St Michael Hospital, Toronto, Canada. Immunofluorescence analysis was perfomed using primary antibodies to detect protein aggregates, neurodegeneration and glial activation: anti‐βAmyloid; anti‐Cleaved‐Casapase3; anti‐PhosphoTau; anti‐Iba1; anti‐GFAP; anti‐C3d; anti‐IL‐1β; anti‐αsynuclein; anti‐TH, anti‐TuJ1.

Result

In all AD patients we detected retinal Aβ and pTau immunoreactivity and both in the inner and outer layers; Aβ plaques number, in a region of 400 mm2, was significantly higher in AD patients compared to controls (p<0.01). pTau immunoreactivity (AT100 clone) was significantly higher in the AD retina compared to age matched controls as quantified by fluorescence intensity in each field of view (p<0.005). Analysis GFAP staining showed a marked astrogliosis localized at the level of the ganglion cell layer both in AD and PD retinas. Astrogliosis may arise also as a consequence of aging however, the amount of astrocyte activation was more pronounced in the AD and PD retina compared to controls, as quantified by fluorescence intensity in each field of view. Similarly microglia cell density was increased in AD and PD patients retina compared to age matched controls. C3 and Il1β were enhanced in bot AD and PD retina, suggesting a detrimental glial activation.

Conclusion

These observations further support the possibility that ocular biomarkers could be used for early detection of AD associated neurodegeneration.
LangAware: A robust ML‐based platform for the quick and accurate assessment of neurodegenerative diseases
Authors: Rentoumi Vassiliki , Paliouras George , Mougias Antonis A. , Kotrotsou Irene , Garrard Peter
Published: December 2020

Background

Although Alzheimer's disease (AD) is associated with changes in spoken language, these have seldom been subjected to systematic analysis on a large scale. We evaluated the effectiveness of LangAware to detect the language indicators that are coupled with early AD, thus assisting with diagnosis. We evaluated LangAware using recordings of speech samples obtained from AD patients and matched healthy controls (NC) derived from various elicitation tasks in two languages, English and Greek*.

Method

English and Greek datasets were analyzed employing feature selection techniques to choose the most prominent multi‐level linguistic analysis features differentiating the AD from the NC group in both languages. The platform’s diagnostic performance was evaluated on its ability to classify "unseen" audio recordings employing these salient features.

Result

Evaluation results indicated that LangAware achieved equally high classification scores for both English and Greek. Most significantly, these scores were achieved by employing a custom set of LangAware‐developed cross‐linguistic markers.

Conclusion

The current evaluation verified the robustness of the platform’s predictive models using audio datasets in two languages. Based on the findings, we conclude that LangAware could provide a time and cost‐effective platform for cognitive screening across languages and across tasks pertaining to neurodegenerative diseases in a range of clinical settings. Such findings also advocate in favor of the robustness of LangAware platform in pursuing cognitive assessment on spontaneous speech across languages. *Peter Garrard and Antonis A. Mougias contributed to this work by providing data for the evaluation of the LangAware platform.
Functional alterations in visual networks underlie differences in the phenomenology of visual hallucinations in Lewy body disease
Authors: D'Antonio Fabrizia , Boccia Maddalena , Di Vita Antonella , Canevelli Marco , Fabbrini Andrea , Leodori Giorgio , Caramia Francesca , Ferracuti Stefano , Guariglia Cecilia , de Lena Carlo , Aarsland Dag , Ffytche Dominic H.
Published: December 2020

Background

The phenomenology of visual hallucinations (VH) in Lewy Body Disease (LBD) is heterogenous including minor phenomena (passage, presence, illusions) and complex hallucinations. Underlying mechanisms are largely unknown and here we investigated whether distinct neural networks underpin minor (MVH) and complex VH (CVH).

Method

LBD patients (n=17 DLB, n=10 PDD; mean age=76.5±6.5; mean MMSE=20.2±5.7, male=16; 59.2%) with VH underwent resting state fMRI and the North East Visual Hallucinations Interview (NEVHI) to assess the phenomenology, duration and frequency of VH. Using multiple regression models, we performed a seed‐to‐seed functional connectivity (FC) analysis to identify specific nodes associated with i) duration, ii) frequency and iii) severity of MVH (controlling for CVH and MMSE) or CVH (controlling for MVH and MMSE).

Result

The severity, frequency and duration of MVH was negatively associated with FC between early visual areas (EVA) and regions of the ventral visual stream, and positively associated with FC between EVA and regions of the dorsal visual stream that may reflect the phenomenology of passage and presence. Furthermore, the duration of MVH was negatively associated with FC between the brainstem and EVA that may be linked to LBD brainstem neuropathology and positively associated with FC between areas of the dorsal visual stream (Table 1). The severity and duration of CVH was negatively associated with FC between areas of the ventral visual stream and positively associated with FC between lingual gyrus and supramarginal gyrus, within the salience network, that may relate to the complexity of the hallucination content. The frequency of CVH was negatively associated with FC between areas of the default mode network and the salience network (i.e. supramarginal gyrus) that may reflect attentional dysregulation (Table 2).

Conclusion

Functional alterations in distinct visual and attentional networks underpin VH in LBD according to their phenomenology, showing a greater involvement of the brainstem and dorsal visual stream for MVH, and of the ventral visual stream and attentional networks for CVH. These findings can be interpreted according to the hodotopic hypothesis of VH (ffytche et al. 2008) and may reflect a link between VH phenomenology and the neuropathological progression of Braak stage (ffytche et al. 2017).
Encapsulated cell biodelivery of NGF (ECB‐NGF) for AD therapy has implications from astroglial activation and amyloid‐beta toxicity
Authors: Mitra Sumonto , Turchetto Silvia , Wahlberg Lars , Linderoth Bengt , Behbahani Homira , Eriksdotter Maria
Published: December 2020

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by loss of cholinergic neurons in the basal forebrain (BFCN). Mature Nerve growth factor (mNGF) is required for the survival of BFCN’s, but since it cannot cross blood‐brain barrier (BBB), its tissue targeted delivery via encapsulated cell biodelivery (ECB‐NGF) device has been envisaged as a potential therapeutic strategy. In our previous first‐in‐human studies, we observed some inter‐capsule differences in mNGF release among ECB‐NGF devices, when implanted in human AD patients. To address this issue, we pursued whether amyloid‐beta (Ab40/42) peptides directly or indirectly (by activating astroglial cells) can affect the NGF‐delivering (NGC‐0211) cells.

Method

We tested direct or astrocyte‐mediated (indirect) effect of Ab40 and Ab42 on the NGC‐0211 cells in‐vitro. To study the astrocyte‐mediated effects of Ab peptides, human primary astrocytes were first incubated with Ab peptides and the conditioned medium was further transferred on NGC‐0211 cells. Effects on cell survival (flowcytometry), stress markers (spectrophotometric measurements), cell proliferation (immunocytochemistry) and NGF release (ELISA) were monitored.

Result

We report that Ab‐peptides induced marginal effects on cell survival and NGF release upon direct and indirect stimulation. Astrocyte conditioned media partially modulated biochemical parameters. In both cases of stimulation method, cell proliferative ability of NGC0211 cells was significantly hampered.

Conclusion

Our data suggests that the survival of the NGC‐0211 cells is not affected by Ab peptides, whereas their proliferation was significantly hampered, directly as well as through astroglial activation. Overall, NGF release was not affected negatively under the conditions and time points tested in this study. This study lays the foundation for further optimization of ECB‐NGF devices for future AD therapy.
Low blood amylin delays Alzheimer’s pathology by modulating brain hypoxia and amyloid composition: A study in humans and rats
Authors: Despa Florin
Published: December 2020

Background

Decreased amyloid‐β (Aβ)42 level in the cerebrospinal fluid (CSF) reflects Aβ42 accumulation in cerebral plaques and is a biomarker for Alzheimer’s disease (AD). Histopathological analyses of brain tissues from individuals with sporadic AD showed that Aβ forms mixed deposits with the pancreatic amylin, a satiety hormone. Here we show that high blood amylin modifies CSF‐brain Aβ balance and brain amyloid composition in both sporadic AD and in PSEN1 and APP mutation carriers (familial AD), and that pancreatic hypersecretion of amylin in AD and non‐AD model rats accelerates behavioral deficits, whereas suppression of amylin expression is protective.

Method

We investigated the relationship between amylin and Aβ42 levels in CSF from humans with early vs. late stage sAD, and between amylin and the brain in PSEN1 and APP mutation carriers, as these mutations have known biochemical effects on AD pathology; experiments in rats and cell models were used to define the mechanism. Specifically, we created transgenic AD and non‐AD rat models in which the consequences of elevated blood levels of human amylin can be directly addressed in terms of CSF‐brain Aβ balance, blood‐brain barrier (BBB) permeability to amylin, development of AD pathology and behavior deficits. To further test the mechanism, we intravenously injected human amylin in AD rats that express rat amylin. AD rats with the amylin gene deleted were generated to test effects of suppression of amylin secretion on AD pathology‐associated neurological score.

Result

We found that high circulating levels of amylin disrupts CSF‐brain Aβ balance via amylin‐Aβ cross‐seeding. Pancreatic hypersecretion of amylin in rats induced brain hypoxia signaling by amylin deposition in brain capillaries that altered neuronal metabolic pathways leading to increased Aβ synthesis and deposition in the brain. Similar mechanisms were triggered by intravenous injection of human amylin in rats. Amylin hypersecretion in APP/PS1 rats lowers neurologic score, whereas amylin gene deletion delays the development of AD pathology and behavioral changes.

Conclusion

Our results provide evidence of a role of amylin in modulating brain hypoxia and amyloid composition in both familial and sporadic forms of AD, and suggest that blood amylin may be a therapeutic target for early AD stage.
Barriers to dementia diagnosis in India: Effect of education, dementia subtype and age at onset
Authors: Ellajosyula Ratnavalli , Narayanan Jwala
Published: December 2020

Background

Early diagnosis in dementia is crucial for management but there is usually a time lag between symptom onset and dementia diagnosis. The prevalence and factors associated with delay in seeking help for people with dementia in India is unknown.

Method

Consecutive patients with dementia (n=924) seen at a memory clinic were enrolled in the study after informed consent. All patients underwent a standard clinical assessment, neuropsychological tests and neuroimaging. The main outcome variable was time from symptom onset to diagnosis (TTD). The effect of age, education, early onset (EOD‐<65 years) and late onset (LOD‐>65 years), dementia subtype, and gender on TTD were examined using a general linear model.

Result

The mean age of the whole group was 70.15(9.1) years and the mean TTD was 32.2 (26.6) months. There was a significant effect of age at onset (EOD 37.2 months vs LOD 27 months), education [(0‐4 years‐37.9 months) vs (5‐12 years ‐27.42 months)] and dementia subtype. Patients with vascular dementia (25.4months) and dementia with Lewy bodies (23.5 months) presented earlier as compared to patients with Alzheimer’s disease (33.4 months) and Frontotemporal dementia (36.8 months).

Conclusion

People with dementia in India are diagnosed much later, approximately 3 years after symptom onset as compared to other Western and Asian studies (1‐2 years). Clinical features and low education may be barriers to seek help for dementia diagnosis.
Amyloid aggregation and subsequent memory decline over time in cognitively intact older identical twins
Authors: Tomassen Jori , den Braber Anouk , Yaqub Maqsood , Mulder Sandra D. , Teunissen Charlotte E. , Van Berckel Bart N.M. , Boomsma Dorret I. , Scheltens Philip , Tijms Betty M. , Visser Pieter Jelle
Published: December 2020

Background

Older individuals with intact cognition and pathological amyloid depositions are at increased risk for memory decline. At this point the precise biological processes leading to cognitive decline are unclear. We tested the role of genetic influences on the relationship between amyloid pathology and subsequent memory decline over time using a monozygotic twin approach, and whether these relationships were dependent on the methodology used to determine amyloid aggregation.

Method

We selected 78 monozygotic twins with at baseline normal cognition from the EMIF‐AD PreclinAD study (Table 1), who had completed 4 years of follow‐up. We defined baseline amyloid status using either visual read of dynamic [18F]flutemetamol PET images or CSF amyloid‐β 1‐42/1‐40 (Aβ42/40) ratio (ADx Neurosciences/Euroimmun assays) <0.066 (based on Gaussian mixture modelling). Memory was tested at baseline, 2‐year and 4‐year, with six tests combined into one composite score. Associations between baseline amyloid status and subsequent decline on memory was tested using linear mixed models with main effect amyloid status, time and amyloid*time, adjusted for age, sex, education and genetic relatedness. We repeated analyses taking continuous CSF Aβ42/40 ratio and PET binding potential (BPND) values as predictors. To examine the role of genetic influences on observed associations we performed cross‐twin cross‐trait analysis.

Result

Nine individuals had abnormal Aβ at baseline and did not differ in age, sex and education from Aβ‐ subjects. They had a faster decline in memory than Aβ‐ subjects (ß=‐0.127(SE=0.041), pamyloid*time=0.002, Figure 1). Continuous measures of amyloid burden also predicted memory decline at follow‐up (CSF Aβ42/40 ratio ß=0.055(SE=0.016), PET BPND ß=‐0.040(SE=0.014), both p<0.005). Baseline CSF Aβ42/40 ratio in one twin could predict memory decline in its co‐twin (r=0.31,p=0.04), which suggests similar genetic factors underlie these processes, however this relation did not reach significance when using amyloid‐PET BPND (r=‐0.12,p=0.35).

Conclusion

In our study CSF Aβ42/40 ratio was more sensitive for detecting early pathophysiological changes compared to PET BPND. A larger sample is needed to confirm this finding. Our twin approach suggests that in preclinical AD amyloid burden and memory performance may share common genetic pathways. The next step will be to identify what these underlying shared biological mechanisms are.