bluuebunny/crossref_metadata_2025 huggingface dataset:
Gamma stimulation improves sleep in Alzheimer’s patients as assessed by continuous actigraphy recordings over six months
Authors: Cimenser Aylin , Hempel Evan , Travers Taylor , Williams Martin , Hajos Mihaly , Malchano Zach
Published: December 2020

Background

Previous work has shown that sleep abnormalities are associated with Alzheimer’s Disease (AD) in multiple ways, including the observation that sleep disruptions precede the onset of cognitive symptoms in AD subjects, and that there is a strong association between disrupted sleep and development and progression of AD (Ju et al, Nat Rev Neurol. 2014 Feb; 10(2): 115‐119, Lim et al, Neurodegener Dis Manag. 2014; 4(5):351‐362). These associations, along with the fact that sleep disturbances can have broad behavioral effects, have led to the suggestion that improving sleep is an important aspect of therapeutic strategies for subjects with AD. In the present study, the long‐term effects of non‐invasive gamma sensory stimulation (Cognito Therapeutics, Inc) on sleep were evaluated in mild to moderate AD patients.

Method

Activity of mild to moderate AD patients was monitored continuously with a wrist worn actigraphy watch, and data was collected during a 6‐month period. Patients were randomized to receive either 40Hz non‐invasive audio‐visual stimulation or placebo treatment. The durations of rest periods during the night was estimated from the actigraphy data and the distributions of these durations were compared between the first 3 months of the treatment period and the second 3 months of the treatment period in both cohorts.

Result

Analysis of the actigraphy data revealed that sensory‐evoked gamma stimulation improved sleep as assessed by continuous actigraphy recordings. In the active treatment group, the distribution of rest‐durations was shifted towards longer durations in the second 3 months compared with the first 3 months. In the placebo group the reverse was observed: the distribution of rest periods was shifted to shorter durations compared in the second 3 months to the first 3 months. The overall total sleep‐time at night was unaltered in either group.

Conclusion

Gamma stimulation therapy over six months demonstrated an improvement in sleep quality and increased night‐time restful periods as assessed by continuous actigraphy recordings.
Clioquinol reduces tau phosphorylation and oligomerization
Authors: Zhu Feiyan , Lin Gaoping , Hamano Tadanori , Kanaan Nicholas M. , Yen Shu‐Hui , Asano Rei , Shirafuji Norimichi , Sasaki Hirohito , Enomoto Soichi , Yamaguchi Tomohisa , Ueno Asako , Ikawa Masamichi , Yamamura Osamu , Nakamoto Yasunari
Published: December 2020

Background

The pathological features of AD are neurofibrillary tangles (NFTs) composed of highly phosphorylated tau and senile plaques (SPs) composed of amyloid β protein (Aβ). It was suggested that Cu2 + induced hyperphosphorylation of tau and Zn2 + deposits on SPs. Clioquinol (CQ) has a mild chelating effect on Zn2 + and Cu2 +. In addition, CQ has been shown to reduce Aβ aggregation by removing Zn2+ from SPs. However, the effect of CQ on tau aggregation is not fully understood. The purpose of our study is to examine the effect of CQ on tau metabolism by using a cell culture model of tauopathy.

Methods

Human neuroblastoma cell line M1C cells that express wild‐type tau protein (4R0N) via tetracycline (Tet) off induction was used. M1C cells were exposed to 0.1‐10 μM CQ on day 4 of Tet‐Off induction, and harvested at the end of Day 5. Total tau detected by Tau5, and phosphorylated tau detected by PS199/202, AT180, AT270, CP13, and PHF‐1 antibodies, were examined using Western blot analysis. Immunocytochemical studies, fractional analysis and immunoprecipitation of ubiquitinated tau were also performed. Tau kinases including c‐Jun N‐terminal kinase (JNK), and P38 MAPK and tau phosphatase, protein phosphatase 2A (PP2A) were also examined. C‐terminal truncated pathological tau was detected by using the antibody TauC3. In addition, autophagy and proteasome activity were also examined.

Result

Phosphorylated tau levels were reduced by 1‐10 μM CQ treatment. Tau kinases, JNK and p38 MAPK were inactivated by CQ treatment. Interestingly, activation of the tau phosphatase PP2A was also observed with CQ treatment. Fractionation studies showed that CQ treatment reduced AT180 and AT270 positive high molecular weight tau in the Tris‐insoluble, sarkosyl‐soluble fraction. CQ also reduced tau oligomer specific antibody TOC1‐positive oligomeric tau. CQ reduced caspase‐cleaved tau detected by antibody TauC3. P62 levels were reduced by CQ treatment, suggesting that CQ activates autophagy. In addition, CQ slightly reduced high molecular weight ubiquitinated tau. This implies activation of the ubiquitin‐proteasome by CQ.

Conclusion

CQ could provide beneficial effects against pathogenic forms of tau via multiple mechanisms and may represent a viable therapeutic approach for AD and other tauopathies.
Comparison of sub‐tests in working memory index among posterior cortical atrophy, Alzheimer’s disease and age‐associated memory impairment
Authors: Sarutikriangkri Yuthachai , Chokesuwattanaskul Anthipa , Phanthumchinda Kammant , Likitjaroen Yuttachai
Published: December 2020

Background

Posterior cortical atrophy (PCA) is a rare syndrome of Dementia. Typically, the main symptoms is visuoperceptual impairment. However, working memory impairment has also been reported. This study aimed reveal the pattern of working memory index impairment in PCA by comparing to Alzheimer’s disease patients (AD) and Age‐associated Memory Impairment subjects (AAMI).

Method

Patients were recruited from Neurocognitive Clinic, King Chulalongkorn Memorial Hospital. Working Memory Index (WMI) in Wechsler Adult Intelligence Scale – Fourth Edition (WAIS‐IV) was used to assess working memory. WMI is composed of 2 subtests which are Digit Span (DS) and Arithmetic (AR). DS is divided into 3 tasks including Digit Span Forward (DSF), Digit Span Backward (DSB), and Digit Span Sequencing (DSS). The score of WMI and all subtests were converted to standard score by age‐matched group. Descriptive statistics, One‐way ANOVA, and Wilcoxon Sign Test were used to analyze.

Result

There were 7 PCA, 19 AD, and 22 AAMI. WMI score of PCA, AD, and AAMI were 65.86, 91.63, and 99.50 respectively. WMI score of PCA were significantly less than AD (p<0.001) and AAMI (p<0.001). For each subtest scaled score of WMI revealed PCA had DS and AR significantly less than AD (p=0.001) and AAMI (p<0.001). Regarding the scaled score of PCA patients, DS was 4.57 (DSF=7.86, DSB=5.29, and DSS=3.57) and AR was 3.57. DSB and DSS were significantly less than DSF (p≤0.05).

Conclusion

Working memory in PCA patients was extremely low compared to AD and AAMI patients. PCA patients were more impaired in mental manipulation and calculation compared to attention. We should consider PCA as a differential diagnosis in dementia patients who score very low on WMI.
Detecting MCI using real‐time, ecologically valid data capture methodology: How to improve scientific rigor in digital biomarker analyses
Authors: Hong Junyuan , Kaye Jeffrey , Dodge Hiroko H , Zhou Jiayu ,   ORCATECH
Published: December 2020

Background

Early identification and accurate assessment of Mild Cognitive Impairment (MCI) is critical for clinical‐trial enrichment as well as the early intervention of the neurodegenerative disease. Continuous home‐based measurements of functions using simple embedded sensors and devices could provide an opportunity to improve the sensitivity and specificity in identifying MCI subjects in the community. However, a large number of assessment data points from each individual might increase the possibility of a chance finding. Careful and creative approaches are required to confirm robustness of the findings.

Methods

A total of 152 participants enrolled in the Intelligent Systems for Assessing Aging Changes Study (ISAAC) from the Oregon Center for Aging and Technology (ORCATECH) were used in the current project. In‐home monitored functional measurements including daily average walking speed, walking variability, computer usage and other functional measures were used. Each subject contributed 1372 days of data on average (SD = 662.3). In order to reflect the fact that various stages of MCI and NC are enrolled into trials in real‐world, longitudinal trajectories from each participant was sliced into small pieces, i.e., slicing windows of different sizes and used for cross‐validation. The cross‐validation was conducted on randomly permutated left‐out validation data to evaluate the performance. We also examined proportion of missingness during each slicing window and examined its impact on the ability in identifying MCI. We used various feature selection methods including F1‐score, mutual information, and chi2 to rank the effectiveness of variables. From the selected variables, we constructed different machine learning models, including logistic regression and support vector machines.

Results

Models using top‐4 features gave the best ability in differentiating MCI from NC, indicated by Receiver Operating Characteristics Area under Curve. Using slicing windows with a missing ratio higher than 30% was found to compromise the model performance. Longer subsequences have more information for modeling, but subsequences longer than a 2‐month window did not further help the performance.

Conclusions

This study proposed an approach that effectively detects MCI from in‐home monitoring measurement, which could benefit study enrichment in preclinical trails. The approaches presented could aid in improving scientific rigor of digital biomarker analyses.
Social isolation and incident dementia in Mexican elders
Authors: Sánchez Brenda Sarai Miranda , Acosta‐Castillo Gilberto Isaac , Ortiz Ana Luisa Sosa
Published: December 2020

Background

Social isolation (SI) (defined as infrequent social contact or people with limited social networks) has been association with cognitive impairment, however, some authors has argued there is not a relationship between both. In line with the World Health Organization (WHO). Dementia is a syndrome affecting memory, thinking, orientation, comprehension, judgement and so on that interfere significantly in the person’s activities of daily living and it is not a normal part of ageing. WHO, points out two in three people with dementia live in low‐and middle‐income countries like Mexico. Indeed, Dementia has a physical, psychological, social, and economic impact on people with it, but also on their families and society.

Method

We analyzed data from 1,355 adults aged 65 or over, evaluated in incidence phase of Dementia Research Group 10/66 protocols in Mexico. Dementia was evaluated according to 10/66 algorithm. Statistical analysis consisted in to compare incident dementia in both groups with and without SI considering: sex, age, education, marital status, home services, disability, depressive symptoms and feelings of loneliness as possible confounding.

Result

The incidence rate in whole sample was 32.5 cases per 1000 person‐years, in presence of SI the incidence was 36.8 cases and in absence of SI was 28.2. When we estimate the association between SI and incident dementia the incidence cumulative ratio was 1.28 and the 95% confidence interval was from 0.92 to 1.79. Also, non‐significance was shown when we adjusted for other variables of interest that previously have been reported as risk factors or predictors for dementia (e.g. age, mild cognitive impairment, neuropsychiatric symptoms, diabetes and feelings of loneliness).

Conclusion

The present study didn’t find a significant relationship between SI and incident dementia. Is important to consider other conditions to improve quality of life in elders, include the social sphere such as loneliness or social support (not analyzed here). Also is important to generate new research about SI independently to know more about this phenomenal and its consequences on elders’ health.
Plasma alpha synuclein (a‐syn) as a potential biomarker of diseases with synucleinopathy
Authors: Senanarong Vorapun , Wachirutmangur Lertchai , Rattanabunnakit Chatchawan , Srivanitchapoom Prachaya , Udomphanthurak Suthipol
Published: December 2020

Background

Alpha‐synuclein (a‐syn) is present in red blood cells, cerebrospinal fluid (CSF), plasma and saliva, in both monomeric and oligomeric forms. Alterations in a‐syn levels in CSF and plasma of Parkinson disease (PD) patients have claimed to be potential PD biomarkers. We explored that a‐syn in plasma was a potential biomarker for synucleinopathy diseases

Method

a‐syn levels in plasma from 54 Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) patients (28 men), 31 Alzheimer disease dementia (AD) (16 men), and 28 controls (3 men) were measured by enzyme‐linked immunosorbent assay (ELISA).

Result

The mean(SD) age of synucleinopathy group, AD group, and normal controls was 72.70(7.72), 74.26(10.37), 62(10.68) (ANOVA test, p<0.001) We showed that the 50th percentile levels of a‐syn were 9.72 ng/ml, 16.78 ng/ml, 16.75 ng/ml in synucleinopathy group, AD group, and normal controls respectively (p<0.001 by Shapiro‐Wilk test of normality in each group). Pairwise comparisons of group diagnosis revealed that between PDD+DLB vs controls: test statistic ‐16.67, SE 7.63, SD ‐2.19, p=0.03; between PDD+DLB vs AD: test statistic 17.21, SE 7.38, SD 2.33, p=0.02; and between controls vs AD: test statistic 0.63, SE 8.54, SD 0.06, p=0.95. The means plasma a‐syn levels in synucleinopathy group (n=54), AD (n=31) group, and controls (n=29) were 21.89(38.84), 38.45(47.79), 34.02(43.97) ng/ml accordingly (ANOVA test, p=0.18). The levels in synucleinopathy group were lower than those in AD and controls. There was a fair correlation between levels of plasma a‐syn and sum of UPDRS part3 (spearman correlation coefficience r=‐0.32, p=0.008) but not with cognition measured by Addenbrook scale. When eliminating the outliers, the area under the receiver operating characteristic curve (ROCwas 0.710 between PDD+DLB vs non synucleinopathy group (AD+NC) (SE=0.052, p=<0.001). At the cut off levels of 11.4 ng/ml indicated sensitivity of 58%(95%CI 43.21%‐71.81%), specificity of 84.78%(95%CI 71.13%‐93.66%), positive predictive value (PPV) of 80.56%, negative predictive value(NPV) of 65%, and accuracy of 70.83%.

Conclusion

The present results suggested that plasma a‐syn could be a potential biomarker for synuclienopathy diseases.
Amyloid‐β, tau, synaptic dysfunction, neurodegeneration, glial and vascular biomarkers in the preclinical stage of the Alzheimer’s continuum
Authors: Suárez‐Calvet Marc , Milà‐Alomà Marta , Salvadó Gemma , Gispert Juan Domingo , Vilor‐Tejedor Natalia , Grau‐Rivera Oriol , Sala‐Vila Aleix , Sanchez‐Benavides Gonzalo , Arenaza‐Urquijo Eider M , Crous‐Bou Marta , González‐de‐Echávarri José Maria , Minguillón Carolina , Fauria Karine , Simon Maryline , Kollmorgen Gwen , Rodríguez‐Lantero Juan , Ashton Nicholas J , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis ,   the ALFA study
Published: December 2020

Background

Alzheimer’s disease (AD) comprises a preclinical stage characterized by pathophysiological changes that occur decades before symptoms arise. Despite the importance of this stage, the biological pathways involved are not yet well understood. The main aim of this study is to define the pathophysiological processes, as measured by CSF biomarkers changes, that occur in the preclinical stage of the Alzheimer’s continuum in a finely‐characterized cohort of cognitively unimpaired individuals.

Methods

We measured a comprehensive set of CSF biomarkers that reflect different pathophysiological processes in 381 cognitively unimpaired participants aged between 49 and 73 years of the ALFA+ study (61% women; 53% APOE‐ε4 carriers; 34% Aβ positive). Specifically, we measured CSF biomarkers related to amyloid‐β (Aβ42, Aβ40) or tau (p‐tau, t‐tau) metabolism, neuronal and axonal damage (NfL), synaptic dysfunction (neurogranin), neuroinflammation (IL6, MCP1), micro‐ and astroglial markers (sTREM2, YKL40, GFAP, S100), vascular injury (sVCAM1, sICAM1), and total α‐synuclein. Measurements were performed using MSD, NeuroToolKit and Elecsys® immunoassays.

Results

We found that CSF tau‐related (p‐tau and t‐tau) and synaptic dysfunction (neurogranin) biomarkers increase throughout ageing only in Aβ‐positive individuals. In contrast, neuronal injury (NfL), micro‐ and astroglial (sTREM2, YKL40, GFAP) and vascular (sVCAM1, sICAM1) CSF biomarkers increase with ageing both in Aβ‐positive and ‐negative individuals (Fig.1). We modelled the changes in CSF biomarkers as a function of CSF Aβ42/40 ratio, p‐tau and p‐tau/Aβ42, which were used as proxies of disease progression. We observed that the first change that occurs in the Alzheimer’s continuum is a decrease in the Aβ42/40 ratio. Shortly after this ratio becomes positive, there is a steep increase in CSF p‐tau, t‐tau, neurogranin and, to lesser extent, in CSF NfL and glial biomarkers (Fig. 2).

Conclusion

Our results show that multiple biological pathways are altered very early in the Alzheimer’s continuum, but differ in their association with Aβ pathology. Whereas CSF tau‐related and synaptic dysfunction biomarkers change promptly and specifically when there is underlying Aβ pathology, CSF NfL and glial biomarkers have a less pronounced and specific increase. Altogether, our results suggest that different biological pathways could be targeted during the preclinical stage of the Alzheimer’s continuum.
Cross‐cultural neuropsychological assessment in Europe: A Delphi expert study
Authors: Franzen Sanne , Nielsen Rune , van den Berg Esther , Papma Janne M.
Published: December 2020

Background

Performance on traditional neuropsychological tests is influenced by factors such as culture, language, (quality of) education, and literacy. As Europe is becoming increasingly diverse, neuropsychological assessment practices need to be adapted to these diverse populations. The aims of this study were to examine the current state of cross‐cultural neuropsychological assessment in Europe and to provide recommendations for researchers and policy makers on this topic.

Method

Twelve experts from nine European countries participated in a Delphi study involving two survey rounds and a group discussion stage. The surveys consisted of open‐ended questions and importance ratings (score out of 10).

Result

Across Europe, several cross‐cultural (adaptations of) neuropsychological tests are available, as well as a limited number of initiatives for training. The main priorities that were identified were the development of tests (median importance rating 10, Q1‐Q3: 9‐10) and norms (median importance rating 9, Q1‐Q3: 8‐10), as well as training, awareness and knowledge among European neuropsychologists (median importance rating 9, Q1‐Q3: 8‐10). According to the Delphi panelists, future focus should be on tests of social cognition (median 9, Q1‐Q3: 8‐10) and language (median 9, Q1‐Q3: 7‐10), closely followed by other domains, such as executive functioning (median 8, Q1‐Q3: 8‐10).

Conclusion

European experts agree that developing tests should be a priority, in particular tests of social cognition and language. European guidelines should be established for working with interpreters in a neuropsychological assessment. Furthermore, training needs to be improved across Europe. A list of recommendations was generated describing essential skills and knowledge necessary for cross‐cultural neuropsychological assessment.
SORL1‐variant carriers in ADES‐ADSP: A higher level of variant pathogenicity associates with earlier age at onset of Alzheimer's disease
Authors: Holstege Henne , Hulsman Marc , Charbonnier Camille , Grenier‐Boley Benjamin , Quenez Olivier , Ahmad Shahzad , Amin Najaf , van Rooij Jeroen G.J. , Grozeva Detelina , Norsworthy Penny , Hummerich Holger , Kawalia Amit , Mok Kin Y. , Shoai Maryam , Dols‐Icardo Oriol , van Der Flier Wiesje , Sims Rebecca , Amouyel Philippe , Hardy John , Clarimon Jordi , Mead Simon , van Swieten John C. , Ramirez Alfredo , van Duijn Cornelia M. , Williams Julie , Nicolas Gaël , Bellenguez Céline , Lambert Jean‐Charles ,   ADSP Consortium
Published: December 2020

Background

Recent reports indicated that extremely rare protein truncating or missense variants in the SORL1 gene are associated with an increased risk and possibly a causative effect on developing Alzheimer’s Disease (AD). Here, we investigated the relationship between the predicted variant pathogenicity and the age at AD onset (a.a.o.) in the largest whole exome sequencing (WES) dataset of AD cases and controls world‐wide.

Method

We combined sequencing data from the ADES and ADSP consortia on a single server. After quality control and exclusion of carriers of pathogenic variants in genes associated with Mendelian inheritance of AD, 12,675 AD cases and 8,693 controls were available for analysis. Non‐synonymous variants were scored using the REVEL algorithm, and loss‐of‐function (LOF) variants were predicted using LOFTEE. The variant‐burden was determined across all genes and odds ratios (OR) for AD‐status were calculated using a multinomial logistic test across age groups.

Result

Of all genes in the genome, rare variants in the SORL1 gene had the strongest association with AD (p = 6.4 × 10−14). We identified 320 rare nonsynonymous missense and loss‐of‐function SORL1 variants (MAF<1 × 10−4). The carrier frequency in AD cases with a.a.o. <65, a.a.o. >65 and cognitively healthy controls was respectively 1.9%, 1.3%, 0.7%. Carrying a SORL1 variant associated with an increased risk of early onset AD (Figure A). Specifically, carriers of LOF variants had a median a.a.o. of 63 years (Figure C), and this associated with a 24.8‐fold increased chance of developing AD before 65 years compared to non‐carriers (Figure B). The median a.a.o. for carriers of nonsynonymous variants with REVEL>75 was 70 years, and such variants associated with estimated 7.6‐fold increased risk of developing AD between 65‐70 years (Figure B). Variants with lower REVEL scores associated with a lower AD‐risk.

Conclusion

The abundance of predicted pathogenic SORL1 genetic variants and the profound effect on AD risk makes the SORL1 protein product a promising target for the design of selective treatment strategies for affected individuals. Further, our results open the discussion of whether and how AD‐affected SORL1‐variant carriers and their (presymptomatic) family‐members should be clinically counselled. For this, pathogenicity screens that distinguish between pathogenic and non‐pathogenic non‐synonymous variants are warranted.
AHEAD 3‐45 study design: A global study to evaluate the efficacy and safety of treatment with BAN2401 for 216 weeks in preclinical Alzheimer’s disease with intermediate amyloid (A3 trial) and elevated amyloid (A45 trial)
Authors: Aisen Paul S. , Zhou Jin , Irizarry Michael C. , Kramer Lynn D , Swanson Chad J. , Dhadda Shobha , Rabe Martin , Krause Stephen , Li David JianJun , Raman Rema , Donohue Michael C. , Sethuraman Gopalan , Johnson Keith A. , Sperling Reisa A.
Published: December 2020

Background

Aβ pathologies occur years prior to cortical tauopathy, neurodegeneration, and clinical symptoms. BAN2401 is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to soluble Aβ aggregated species (oligomers, protofibrils). BAN2401 reduced amyloid on PET and slowed cognitive decline in a Phase 2 study in early symptomatic AD. The AHEAD 3‐45 study will test the safety and efficacy of BAN2401 even earlier in the AD continuum.

Method

AHEAD 3‐45 consists of two trials (A3 Trial and A45 Trial) under a single protocol and screening process, common schedule of assessments, and distinct dosing regimens tailored to the baseline amyloid level. The study is a Public‐Private Partnership of the Alzheimer’s Clinical Trial Consortium (ACTC), National Institutes of Health (NIH), and Eisai, Inc. The A3 Trial will enroll cognitively normal individuals (CN) with intermediate amyloid (approximately 20‐40 centiloids), at risk for further amyloid accumulation and development of neurofibrillary tangles on tau PET over four years. Approximately 400 participants will be randomized 1:1 to placebo or BAN2401 infusion—8 weeks of titration followed by 10 mg/kg every four weeks for 216 weeks. The A45 Trial will enroll CN individuals with elevated amyloid, defined as amyloid PET approximately >40 centiloids, at risk for cognitive decline over four years. Approximately 1000 participants will be randomized 1:1 to placebo or BAN2401 infusion—8 weeks of biweekly titration dosing, then 10 mg/kg biweekly induction dosing through 96 weeks to clear aggregated Ab, followed by 10 mg/kg every four weeks maintenance dosing through 216 weeks to prevent reaccumulation of Aβ.

Result

Longitudinal cognitive, safety, amyloid and tau PET, MRI and fluid biomarker assessments will be performed. The primary outcome of the A3 Trial is prevention of brain amyloid accumulation by amyloid PET at 216 weeks, with delay of tau PET accumulation as a key secondary outcome. The primary outcome measure of the A45 Trial is the Preclinical Alzheimer’s Disease Cognitive Composite 5 (PACC5) scale at 216 weeks.

Conclusion

The AHEAD 3‐45 Study will test whether BAN2401 can prevent the accumulation and spread of Aβ deposition, downstream tau pathology, and cognitive decline in at‐risk cognitively normal individuals prior to significant irreversible neurodegeneration.
Impact of mild head injury on diffusion MRI brain characteristics in midlife: Data from the PREVENT Dementia Study
Authors: Raymont Vanessa , O'Donoghue M Clare , Mak Elijah , Dounavi Maria‐Eleni , Su Li , MacKay Clare , O'Brien John T , Ritchie Craig W
Published: December 2020

Background

Traumatic brain injury (TBI) has been associated with an increased risk of dementia, but the link between mild TBI across the life‐course remains unclear. The PREVENT Dementia study is recruiting healthy volunteers in middle age (aged 40 – 59) to identify factors that may increase their risk of dementia. This analysis assessed white matter integrity and its association with the incidence, frequency and severity of TBIs.

Methods

140 subjects (mean age=51.9 years) from the PREVENT Dementia study West London site underwent a 3T MRI scan, including diffusion‐weighted (DW) imaging, and completed the self‐report Brain Injury Screening Questionnaire (BISQ). DW images were processed using FSL tools (EDDY, DTIFIT, TBSS) and resulting fractional anisotropy (FA) and mean diffusivity (MD) spatial maps were fed into voxelwise cross‐subject analysis (FWE‐corrected at p<0.05). BISQ summary scores were used as regressors in cross‐subject analyses to test the effect on WM integrity of a) no TBI (N=29) vs. any TBI (N=107), b) number of TBIs, and c) severity of TBIs. Gender, years of education, NART score, presence of psychiatric diagnoses and substance abuse were included as covariates. One participant with severe TBI (BISQ severity=6) and three participants with moderate TBI (BISQ severity=4) were excluded from analyses.

Results

Higher FA was observed in bilateral body of the corpus callosum, superior corona radiata and forceps minor in those that reported at least one TBI compared to those that had none. There was no effect of this on MD. There was no significant association of the number of TBIs with either FA or MD. However, increased severity of TBI was significantly associated with higher FA in similar regions showing an effect of any vs. no TBI. Increased severity of TBI was also significantly associated with lower MD in the same regions.

Conclusions

It is unclear if higher FA reflects a mechanism of recovery post‐TBI or the injury itself. We plan to analyse a larger sample, as this sub‐group may not be representative, and include other possible confounders, such as cognition and age of and time since injury, to explore what these results may infer about mild TBI and dementia risk.
Assessment of intracranial vascular flow oscillations in Alzheimer’s disease using real time 4D flow MRI
Authors: Rivera Leonardo A , Eisenmenger Laura , Cary Paul , Johnson Sterling C. , Johnson Kevin M
Published: December 2020

Background

Recent models suggest clearance of soluble metabolites from the brain can be driven by low frequency flow oscillations (LFO) of vascular smooth muscle cells through the intramural periarterial drainage (IPAD) pathway. This work derives LFO from measures of blood flow variance using real time 4D flow MRI in the intracranial arteries of clinically diagnosed Alzheimer’s disease (AD) subjects.

Methods

Subjects: Study groups are summarized in Figure 1. The APOE4+,FH+ group consisted of healthy late middle‐aged subjects with both APOE ε4 allele and parental family history of AD dementia positive. MRI: Volumetric, time‐resolved 4D flow MRI data were acquired on a 3.0T system (MR750, GE Healthcare) using a 32‐channel head coil (GE Healthcare). Images were reconstructed to a spatial resolution of 1.38mm isotropic and a temporal resolution of 4.3sec (scan time=7.1min). To evaluate the ability of 4D flow to distinguish physiologic flow changes from noise, healthy volunteers were scanned during a scan with breath‐holds (BH). LFO analysis: Flow waveforms in the internal carotid artery (ICA) and superior sagittal sinus (SSS) were recorded from the dynamic data. To quantify LFO demeaned temporal flow changes and standard deviations were calculated. Global atrophy was estimated as the ratio of CSF volume to brain volume. Group differences were assessed using ANOVA followed by Tukey‐Kramer method for pairwise comparison for adjusted means (P<0.05).

Results

Figure 2 shows an example of flow curves from a young volunteer during free breathing and a scan with BHs. Flow variance increased during the BH scan. The ICA flow variance normalized to the intracranial volume (ICV) and global atrophy, and ICA blood flow ranges were significantly larger in age‐matched controls compared to AD (P=0.025, P=0.024, P=0.004) (Figures 3&4). LFO from demeaned flow profiles are shown in Figure 5 for all subjects. The LFO in age‐matched controls were noticeable larger than in AD subjects. Finally, average flow rates in age‐matched controls were significantly larger than in AD subjects in the ICA (P=0.034) (Figure 6).

Conclusions

Significantly higher LFO, as measured by standard deviations, are measurable in age‐matched controls when compared to AD subjects suggesting decreased vascular compliance and vasomotion in AD.
A novel type of amyloid‐beta plaques discovered in early‐onset AD patients
Authors: Boon Baayla D.C.
Published: December 2020

Background

The clinical presentation of Alzheimer’s disease (AD), including age at onset, is remarkably heterogeneous. Besides clinical heterogeneity, we recognize distinct Aβ deposits in AD pathology. These deposits are called plaques when located in brain parenchyma or cerebral amyloid angiopathy (CAA) when located in cerebral vessels. Recently, we described a novel Aβ plaque‐type, referred to as ‘the coarse‐grained plaque’. In this study, we evaluate its clinical relevance and perform in‐depth morphological characterization.

Method

The coarse‐grained plaque’s presence was investigated in the frontal cortex of Aβ‐pathology‐positive cases (N = 74), including non‐demented controls (n = 15), early‐onset (EO)AD (n = 38), and late‐onset (LO)AD (n = 21), using a semi‐quantitative approach. Main plaque characteristics were compared to other well‐defined Aβ deposits; the classic cored plaque, the cotton wool plaque, and CAA. In‐depth characterization was done by studying the coarse‐grained plaque’s Aβ isoform (Aβ40, Aβ42, AβN3pE, and pSer8Aβ) composition, neuroinflammatory component, and vascular association using immunohistochemistry and 3D confocal laser scanning microscopy imaging.

Result

The plaque was only observed in cases with clinical symptoms, it was more prominent in EOAD (95%) than in LOAD (66%) and was associated with a homozygous ApoE4 status (Figure 1). The coarse‐grained plaque showed a multi‐cored Aβ morphology and was seen in the proximity of CAA‐affected sulci. Its predominant Aβ40 composition was distinct from other plaques, but showed similarities to that of CAA (Figure 2A). 3D imaging revealed a unique hollow Aβ40‐shell structure (Figure 2B) with microglia in Aβ‐devoid holes (Figure 3). Furthermore, the plaque’s immunoreactivity for the CAA‐Type 1 specific marker norrin suggests – although having a different morphology ‐ a close etiological relation with CAA.

Conclusion

The coarse‐grained plaque is a clinically relevant Aβ deposit as it occurs only in clinical AD and is more frequent in EOAD. The plaque is strongly associated with neuroinflammatory and vascular changes. Differences in presence of coarse‐grained plaque among AD subtypes, contributes to the compiling evidence that also pathophysiology in AD is heterogeneous.
Structural brain network efficiency and cognitive processing speed in healthy aging
Authors: Seiler Stephan , Fletcher Evan , Beiser Alexa S , Himali Jayandra J , Satizabal Claudia L , Seshadri Sudha , Maillard Pauline , DeCarli Charles
Published: December 2020

Background

To test the hypothesis that structural brain network efficiency relates to cognitive processing speed and executive function, we computed structural brain networks of 2,278 healthy adults and conducted graph theoretical analyses.

Method

2,278 healthy adults from the cross‐sectional Framingham Heart Study, aged 26‐91 years, were included. We used the trail making test (TMT) parts A and B to assess processing speed. To assess executive function, we subtracted the TMT A from the TMT B score to obtain the TMT difference score. We computed structural brain networks from MRI, using diffusion tensor imaging (DTI) probabilistic tractography. Graph theory was then applied to assess global network efficiency (GE) and nodal efficiency (NE) of 72 nodes (gray matter regions). Global‐ and nodal relationships between efficiency measures and age, white matter hyperintensities (WMH), and processing speed scores were tested using linear models. All linear models were adjusted for confounding variables. Node‐wise p‐values <0.05, corrected for multiple comparisons, were considered statistically significant.

Result

Higher age was significantly associated with lower GE (β=‐0.143, p<0.001, figure 1.1). Higher WMH volumes related to lower GE, independent of age (β=‐0.069, p<0.001, figure 1.2). Node‐wise regression analysis revealed that associations of age and WMH with NE were differentially distributed across the brain. Efficiencies of widespread cortical and subcortical nodes correlated negatively with age and WMH (figure 2), while nodes including the posterior and caudal cingulate cortex and precuneus correlated positively with age (figure 3), but not WMH (p<0.05, corrected). GE related positively to TMT B (β=0.046, p=0.006, figure 4.1) and the TMT difference score (β=0.039, p=0.012, figure 4.2). Efficiencies of mainly fronto‐temporal, but also subcortical nodes were associated with TMT B and the TMT difference score (p<0.05, corrected, figure 5).

Conclusion

Aging and WMH negatively impact efficiency of the structural brain network. Regional efficiency losses, mainly in fronto‐temporal, but also subcortical nodes, relate to reduced processing speed and executive function. Positive nodal relationships with age might represent a compensatory effect, but this hypothesis needs further exploration.
Different relationship of cross‐regional correlations of progression of local cortical thickness and local SUVR 18F‐Flortaucipir PET values to strength of connectivity
Authors: Soucy Jean‐Paul , Mohammadi Fatameh , Boulier Thomas , Hortelan Valentine , Rosa‐Neto Pedro , Pascoal Tharick A. , Savard Melissa , Kang Min Su , Mathotaarachchi Sulantha , Therriault Joseph , Benali Habib
Published: December 2020

Background

We have demonstrated in vivo in humans that spatial progression of tau distribution and atrophy in Alzheimer’s is largely driven by connectivity (Soucy et al, HAI2020). Nevertheless, local tau accumulation and atrophy should not progress in parallel during disease evolution. Atrophy keeps worsening, while local tau density (SUVRs estimated with PET) initially increases but could then decline because of tissue loss. Therefore, despite the impact of connectivity on progression of both local atrophy and SUVRs, it likely will not remain the same for both over time. This is what we tested in this work.

Method

We studied 35 AD subjects from ADNI with 2 PET studies (18F‐florbetapir) at times Ta/Tb (mean elapsed time = 438 days, median = 454), and a T1 MRI at Ta. Eighteen subjects were non‐progressors (NP) and 17 were progressors (P) based on change between Ta/b hippocampal SUVRs values. This criterion was considered to represent how far advanced patients were in their disease. Moran I statistic was used to measure autocorrelations between connectivity and T1 MRI‐defined cortical thickness at Ta or tau PET SUVR values at both times Ta and Tb in NP and P subjects in regions separately analyzed based the “intensity” of their connectivity as defined by a standard connectivity map (Human Connectome Project). We defined 3 groups of regions from thresholds separating poorly connected from moderately connected (0.01) and moderately connected from highly connected ones (0.021).

Result

In both NPs and Ps, regions with high connectivity showed higher Z‐score (4.06) of the Moran I value for correlations between regions’ cortical thickness than those with low (2.64)/moderate (2.17) connectivity. For SUVR values however, in both NPs and Ps and at both time points, Z‐scores were always lower for the highly connected regions than for those with moderate/low connectivity.

Conclusion

The way connectivity influences correlations of atrophy across regions is indeed different from the way it affects correlations of tau deposition, likely for the reasons we hypothesized above to guide the progression of each parameter. Models of tau propagation across the brain will need to factor in ongoing atrophy but reversible accumulation of tau.
Within and between person effects of sleep quality on daily cognitive performance: Data from the Einstein Aging Study (EAS)
Authors: Derby Carol A , Zhaoyang Ruixue , Jiao June L , Sliwinski Martin J , Buxton Orfeu M
Published: December 2020

Background

Evidence suggests that sleep disturbance may precede cognitive decline and may thus be a target for early intervention. Few studies have examined the short term (day to day) associations between sleep quality and cognitive performance in older adults. The Einstein Aging Study (EAS) provided the opportunity to examine ambulatory measures of sleep (actigraphy) and smartphone based ecological momentary assessments of cognitive performance to examine between‐ and within‐person effects of sleep quality on cognitive performance the following day.

Methods

Analyses involved 224 participants enrolled in the Einstein Aging Study, a community based longitudinal cohort of older adults free of dementia at enrollment (Mean age 77.3 years; 33% male; 47% White, 39% African American, 13% Hispanic). Participants wore an actiwatch, and completed brief smartphone based cognitive assessments 6 times per day over an 18‐day period. Multilevel models were used to examine between‐person and within‐person associations between objective measures of sleep quality (wake after sleep onset (WASO)), and duration with daily mean cognitive performance, adjusted for age, gender, race/ethnicity, education (years), and learning effects. Cognitive performance was assessed using previously validated smartphone based cognitive tests of processing speed (Symbol Match), working memory (Color Dot) and memory binding (Color Shape).

Results

Between person results show that older adults with less nightly WASO on average had better processing speed (b=7.18, p=0.001), better working memory (b=0.001, p=0.005), and better memory binding (b= ‐0.003, p<0.001). Within‐person results showed that higher WASO was significantly associated with worse processing speed the next day: A thirty‐minute increase in nightly WASO predicted a 13 millisecond increased response time on the Symbol Match Test (p=0.001). There were no significant within‐person associations between WASO and working memory or memory binding. Sleep duration was not associated with cognitive performance in any of the analyses.

Conclusions

Within individuals, poor sleep quality is associated with worse cognitive processing speed the following day. The cumulative effects of poor sleep may lead to long term cognitive decline. Future work will determine whether individuals susceptible to the adverse effects of sleep from day to day are at increased risk for long term cognitive decline.
Central nervous system‐active polypharmacy among community‐dwelling persons with dementia in the United States
Authors: Maust Donovan T , Kim H Myra , Strominger Julie , Chang Chiang‐Hua , Langa Kenneth M , Bynum Julie , Kales Helen C , Zivin Kara , Marcus Steven
Published: December 2020

Background

Psychotropic prescribing and central nervous system (CNS)‐active polypharmacy are increasing among community‐dwelling older adults in the United States.1 While psychotropic prescribing to persons living with dementia (PLWD) in long‐term care has received significant regulatory attention, there are no recent estimates of use among PLWD in the community. The aim of this analysis is to determine the prevalence of CNS‐polypharmacy (“CNS‐poly”)—potentially inappropriate for older adults given risks of associated falls and overdose2—among community‐dwelling PLWD.

Method

The cohort included beneficiaries: 1) enrolled in fee‐for‐service Medicare with Part D (prescription drug); 2) with a dementia diagnosis from 10/1/14 – 9/30/15 (the baseline); and 3) who were community‐dwelling (determined by Minimum Data Set). CNS‐poly was defined as receipt of ≥3 medications for ≥31 consecutive days from the following classes: opioids, antipsychotics, antidepressants, benzodiazepines, “z‐drugs”, anti‐epileptics. The CNS‐poly observation period was 10/1/15–9/30/16; as with baseline, those with time in LTC were excluded. We determined CNS‐poly overall and by demographic characteristics, then by state.

Result

Among 740,274 beneficiaries, 14.8% experienced CNS‐poly. The prevalence was higher among: females versus males (16.1% vs 12.2%); younger persons (24.2%, 14.6%, 10.2% for those 65‐74, 75‐84, and ≥85); and non‐Hispanic white and Hispanic beneficiaries compared to non‐Hispanic black and other (15.6%, 15.6%, 9.4%, and 8.8%); but comparable for urban and rural (15.8% vs 15.8%). The Figure presents state‐level prevalence by quintile. The state‐level median was 14.4%, with Hawaii lowest (5.4%) and North Carolina highest (19.1%).

Conclusion

CNS‐poly is widespread among PLWD in the U.S.—much higher than among the general population of older adults1—and varies widely by patient demographics and by state. Future work is needed to understand drivers of this high rate of CNS‐poly and to develop patient, provider, and policy‐level interventions to more appropriately target psychotropic use.
Differential effects of apolipoprotein E on the molecular and cellular phenotypes associated with Alzheimer’s disease in isogenic human iPSC‐derived neurons
Authors: You Yang , Poon Wayne W. , Jun Gyungah R. , Farrer Lindsay A. , Ikezu Tsuneya
Published: December 2020

Background

Apolipoprotein E4 (APOE4) is an established AD risk gene, while APOE2 is considered protective. Recently, several studies demonstrated that APOE4 can induce AD‐related pathological phenotypes including tau phosphorylation (p‐tau), neuroinflammation, and tau‐mediated neurodegeneration in both mouse models and human neurons. However, the underlying mechanism of APOE4 in AD pathology and how other APOE isoforms affect the molecular and cellular phenotypes associated with AD are not well understood in human cells. In this study, we used isogenic human induced pluripotent stem cell (iPSC)‐derived neurons to explore the differential effects of APOE isoforms on AD‐related pathology.

Methods

Isogenic human APOE2/2, APOE3/3, APOE4/4 and APOE knock‐out (APOE‐/‐
) iPSC lines were generated by CRISPR‐Cas9 editing and characterized by immunocytochemistry. Functional excitatory neurons were induced from isogenic iPSCs by overexpressing neural fate‐driven gene neurogenin2, and tested for the expression of AD and neuroinflammation‐related genes, p‐tau, and neuronal firing and synchrony in vitro.

Results

Four isogenic iPSC lines were successfully differentiated into functional excitatory neurons with >99% purity. We found significantly reduced gene expression of C4A and C4B, which have been implicated in AD pathology, in APOE2/2 neurons compared to APOE3/3 (p=0.0377) or APOE‐/‐
neurons (p=0.0284). We also observed an upregulated expression of PPP2CB in APOE‐/‐
neurons compared to three other APOE isogenic neurons (one‐way ANOVA, F=3.863, p=0.0249), suggesting a possible APOE‐dependent suppression of PPP2CB expression. Further, the ratio of the level of p‐tau at both Thr 231 and Thr 181 sites to total tau was significantly lower in APOE3/3 neurons than APOE4/4 or APOE‐/‐
neurons (Thr 231: APOE3/3 vs APOE4/4, p<0.0001; APOE3/3 vs APOE‐/‐
, p=0.0033; Thr 181: APOE3/3 vs APOE4/4, p=0.0071; APOE3/3 vs APOE‐/‐
, p=0.0115). The expression of C4A/B but not PPP2CB was found inversely correlated with the level of p‐tau at the Thr 231 site. Finally, APOE3/3 neurons showed significantly higher neuronal firing activity and synchronization compared to other APOE isogenic neurons, which were resistant to excess glutamate treatment.

Conclusion

Our findings in isogenic iPSC‐derived neurons describe the differential effects of APOE on the expression of AD‐related genes, p‐tau and neuronal functions, which provide new insights into the potential role of the APOEvariants in AD.
Functional indicators of a decline in the noradrenergic locus coeruleus in ageing
Authors: Hammerer Dorothea , Hopkins Alexandra , Ludwig Mareike , Yi Yeo‐Jin , Lüsebrink Falk , Liu Kathy , Femminella Grazia Daniela , Betts Matthew J , Callaghan Martina F , Howard Robert J , Düzel Emrah
Published: December 2020

Background

Postmortem studies show that the locus coeruleus (LC), the major source of cortical noradrenergic projections, exhibits evidence of neurodegeneration early in Alzheimer’s disease (AD). Indeed, the noradrenergic system is more affected than the dopaminergic or cholinergic ones. Albeit to a smaller extent, neuronal loss in the LC is also seen in cognitively normal older adults, which can in some cases reflect the earliest stages of AD neuropathology before cognitive changes are clinically detectable. These postmortem findings have been corroborated in recent years by in vivo assessments of LC integrity using anatomical MRI (magnetic resonance imaging) approaches. Before measurable neuronal loss occurs, functional LC decline should be observable. I will present the results of a series of studies involving pupillometry, high‐resolution fMRI (functional) as well as cognitive paradigms targeting noradrenergic function, which investigated whether a decline in LC function can be detected in cognitively normal older adults.

Method

We examined LC function during an emotional memory task known to rely on the noradrenergic system in 22 healthy younger adults (18‐30 years) and 22 healthy older adults (62‐83 years) with pupillometry (a proxy for LC function) (Study 1), as well as 22 healthy younger adults (20‐31 years) and 28 healthy older adults (65‐84 years), using high resolution fMRI (Study 2).

Result

Our studies reveal both, a) evidence for a decline in functional LC responses with ageing (Figure 1, pupillometric data), as well as, b) evidence for no decline in functional LC responses in older adults (in pupillometry and fMRI). Specifically, reduced LC responses with ageing were observed in experimental conditions that allowed for a more selective assessment of LC function, independent of the engagement of other brain areas, underlining the need for a careful selection of cognitive paradigms when investigating functional indicators of LC decline.

Conclusion

Our results show that fMRI and pupillometry are promising methods for assessing changes in LC function in ageing and early AD. We provide recommendations for cognitive paradigms, experimental setups as well as data analysis methods for researchers interested in assessing functional changes in the noradrenergic system in AD and other disorders.