bluuebunny/crossref_metadata_2025 huggingface dataset:
Data‐assisted differential diagnosis of dementia by deep neural networks using MRI: A study from the European DLB consortium
Authors: Larsen Simen Norrheim , Oppedal Ketil , Eftestøl Trygve , Ferreira Daniel , Lemstra Afina W. , Kate Mara ten , Padovani Alessandro , Rektorova Irena , Bonanni Laura , Nobili Flavio Mariano , Kramberger Milica G. , Taylor John‐Paul , Hort Jakub , Snædal Jón , Blanc Frédéric , Antonini Angelo , Borda Miguel German , Aarsland Dag , Westman Eric
Published: December 2020

Background

Clinicopathological overlap between neurodegenerative diseases contributes to challenging differentiation between dementia types. Improving differential diagnosis is important to provide optimal patient care and better predict future needs. Deep learning techniques such as convolutional neural networks have in recent years gained much attention for their high performance in image classification. Magnetic resonance imaging (MRI) computer‐assisted diagnosis (CAD) systems based on deep learning could potentially contribute to increased reliability of clinical diagnosis.

Method

An ensemble model of 3D‐convolutional neural networks was trained and tested on a class‐balanced dataset consisting of T1‐weighted MRI brain scans for the differentiation of subjects diagnosed with Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and normal controls (NC). Total number of brain scans used for training and testing were 690 (nAD=nDLB=nNC=230) and 171 (nAD=nDLB=nNC=57) respectively. Diagnoses were clinical, not including MRI, and in a subgroup of the DLB patients the diagnosis was supported by DAT scan. All scans were skull‐stripped and spatially normalized. All classes were matched for age and sex. Data augmentation was applied using the left and right hemisphere as separate instances and a Bayesian approach was used for hyperparameter optimization. Experiments were conducted using 6‐fold cross‐validation, with the final model constructed as an ensemble of all models.

Result

A final accuracy of 71.9% was reported for the three‐class differential classification of 171 stand‐out test subjects. The model classified the NC, DLB and AD subjects with 71.9%, 86.0% and 57.9% accuracy respectively. Further inspection showed that most of the miss‐classified AD patients were wrongly classified as DLB by the CAD system.

Conclusion

The results of this work show promising potential for deep learning based CAD systems trained on MR brain images for differential diagnosis of dementia. Most data‐driven dementia classification models, including the one presented in this work, are limited by the amount of available data, comorbidity, and the inaccuracy of clinical diagnosis. Increasing the amount of data might significantly improve such models. The prospective E‐DLB study will provide more brain MRI data for future improvement of the suggested deep learning based CAD system.
PR001 gene therapy improved phenotypes in models of Parkinson’s disease with GBA1 mutation
Authors: Sheehan Patty , Heckman Laura D. , Fenn Tim , Wong Li Chin , Nelson Stuart , Garimalla Swetha , Haller Jorge , Daily Jenn , Politi Jason , Dai Yong , Hefti Franz , Abeliovich Asa
Published: December 2020

Background

Mutations in GBA1, which result in deficiency of lysosomal enzyme glucocerebrosidase (GCase), are the most common known genetic cause of Parkinson’s disease (PD). Decreased GCase activity in PD patients with GBA1 mutations (PD‐GBA) causes accumulation of glycolipid substrates, which leads to lysosomal dysfunction and neuroinflammation. With our gene therapy product candidate, PR001, we aim to increase GCase activity in PD‐GBA patients in order to ameliorate the lysosomal dysfunction and slow or stop disease progression.

Method

GCase activity and α‐Synuclein levels were assessed following PR001 treatment in vitro in a cell line and in primary rodent neurons. Two mouse models of GCase deficiency that display phenotypic characteristics consistent with PD‐GBA, including decreased GCase activity, glycolipid substrate accumulation, motor behavioral phenotypes, and neuroinflammation, were used to assess the efficacy of PR001 in vivo. Safety endpoints were examined in the two mouse models as well as in nonhuman primates.

Result

PR001 treatment in vitro increased GCase activity and decreased α‐Synuclein levels. In PD‐GBA models in vivo, PR001 treatment increased GCase activity, decreased glycolipid substrate accumulation, improved motor abnormalities, and decreased neuroinflammation. These therapeutic benefits were persistent, with lasting effects observed at 6 months post‐treatment. Safety studies demonstrated that PR001 was well tolerated at all doses tested.

Conclusion

Overall, PR001 displayed efficacy in multiple independent cell and animal models of PD‐GBA and no PR001‐related safety events or adverse findings in mice and nonhuman primates. These findings demonstrate that PR001 is a promising potential gene therapy for PD‐GBA patients. We have recently initiated a Phase 1/2 clinical trial to investigate safety, tolerability, and effects on biomarkers and measures of clinical efficacy.
Faster rates of tau accumulation in FTP‐PET in females relative to males, and a cross‐sectional influence on faster cognitive decline: Preliminary findings from HABS and ADNI
Authors: Buckley Rachel F. , Properzi Michael J. , Schultz Aaron P. , Scott Matthew R. , Jacobs Heidi I.L. , Farrell Michelle E. , Kirn Dylan , Hanseeuw Bernard J. , Amariglio Rebecca , Rentz Dorene , Johnson Keith A. , Sperling Reisa A.
Published: December 2020

Background

Clinically normal older females exhibit higher cross‐sectional 18F‐Flortaucipir (FTP)‐PET signal, but not Aβ‐PET, than males, particularly in temporal regions. What remains unclear is the extent to which these findings represent a real biological phenomenon as opposed to a methodological bias. Here, we explored sex differences in longitudinal tau accumulation, and how contemporaneous rates of FTP‐PET, Aβ‐PET and cognitive change may be modified by sex.

Method

We examined 128 clinically‐normal participants from the Harvard Aging Brain Study (HABS; 60% Female, Age=75(6.6)years) with at least two time‐points of contemporaneous FTP‐PET, PiB‐PET and cognition. Also, 153 ADNI participants with at least two time‐points of FTP‐PET (nCN=94/nMCI=59; 50% Female, Age=73(6.4)years), and with prospective longitudinal AV45‐PET and cognition (n=131). Mean follow up was 3.3yrs (range=1.2‐6.2yrs) and 1.4yrs (range=0.6‐3.3yrs), respectively. For FTP‐PET we exclusively examined the inferior temporal lobe (non‐partial volume corrected, cerebellar greyreference), for Aβ‐PET we used the PiB summary measure in HABS (cerebellar greyreference) and the AV‐45 summary measure in ADNI (whole cerebellumreference). For cognition, we used the Preclinical Alzheimer Cognitive Composite (PACC). We examined relationships between contemporaneous longitudinal FTP‐PET, Aβ‐PET, and cognitive performance using linear mixed models, adjusting for age, years of education and random intercept.

Result

In HABS, females exhibited faster rates of FTP‐PET accumulation than males, but only with increasing rates of Aβ‐PET accumulation (t=1.93, p=0.003; see Figure 1A). In ADNI, females exhibited faster rates of FTP‐PET accumulation, not moderated by Aβ‐PETchange (t=2.92, p=0.004; see Figure 1B). Sex did not moderate the relationship between FTP‐PET and PACC change in HABS or ADNI (see Figure 2.). We did, however, find that females with higher baseline FTP‐PET resulted in faster PACC decline than men in only clinically‐normal individuals in both cohorts (t=‐1.86ADNI,‐2.72HABS, p∼0.02; see Figure 3.).

Conclusion

These findings support a female susceptibility to tau as a biological phenomenon of accelerated tau accumulation in AD‐vulnerable regions. A lack of an association between changing tau and changing cognition remains to be understood. It is possible that our models are picking up more on the ‘severity of burden’ (e.g. baseline tau) to influence faster rates of decline in females, rather than dynamic change per se.
Clinical assessment of sleep disorders in elders with Alzheimer’s disease and their relationship with intracranial pressure using a non‐invasive method
Authors: Ribeiro Estela B , Ramos Caio Freitas , Vale Francisco Assis Carvalho , Frigieri Gustavo
Published: December 2020

Background

Literature establishes that sleep disorders (SD) possess strong correlations with Alzheimer’s Disease (AD) derivations and the more resources are found to perform assessments, the better and earlier diagnoses can be performed. Thus, allowing early interventions that could improve the quality of life of the person with AD. This study aims at verifying whether there are alterations in the intracranial pressure (ICP) of elder patients with AD and SD when compared to elders patients with AD but without SD.

Method

The sample was obtained in the Ambulatory of Cognitive‐Behavioural Neurology (ANEC) at UFSCar, in partnership with BrainCare® company, which developed a new method for non‐invasive intracranial pressure measurement.

Result

Most of the sample was composed of females. The most frequent CDR was 3 in the AD Group, indicating a more advanced dementia stage. When analyzing the full group, without subdivisions, a correlation between T2/T1 (p=0,01/ρ=‐0,42) was verified as dimensions that assessed night behavior. More specifically, when the elders were questioned about awakening several times at night and if they had the habit of rising up during the night (p=0,04/ρ=‐0,36). No correlations were found between the ICP assessments and other variables of this study. However, when the subjects were subdivided into patients with SD or without SD, the results were different compared to the general assessment.

Conclusion

Due to the novelty of this study, it was not possible to discuss the findings with previous literature. Nevertheless, the study presents a limitation related to the size of the sample; a widening of the sample size would possibly have led to different findings. Although no difference between patients with AD and TS was found in the assessment of the ICP morphology, there was a difference between the groups with AD and without AD. Similar studies should consider expansion and evaluation within different contexts.
Association between cerebral amyloid accumulation and synaptic density in Alzheimer’s disease: A multitracer PET study
Authors: O'Dell Ryan S. , Mecca Adam P. , Chen Ming‐Kai , Godek Tyler A. , Harris Joanna E. , Bartlett Hugh H. , Banks Emmie R. , Kominek Victoria L. , Zhao Wenzhen , Naganawa Mika , Toyonaga Takuya , Lu Yihuan , Nabulsi Nabeel B. , Ropchan Jim R , Ye Yunpeng , Vander Wyk Brent C. , Varma Pradeep , Arnsten Amy F.T. , Huang Yiyun , Carson Richard E. , van Dyck Christopher H.
Published: December 2020

Background

Synaptic loss is an early pathology in Alzheimer’s disease (AD) and the major structural correlate of cognitive impairment. We have recently demonstrated extensive synaptic loss in medial temporal and neocortical brain regions of participants with AD. In this study, we further investigate the association of global and local amyloid burden with synaptic density in AD using [11C]UCB‐J PET.

Method

[11C]UCB‐J and [11C]PiB binding were measured in 38 participants with AD and 19 cognitively normal participants aged 55‐85 years. For [11C]PiB analysis, parametric images of binding potential (BPND
) were generated using SRTM2 with cerebellum as a reference region and converted to distribution volume ratios (DVR). For [11C]UCB‐J, BPND
was computed using SRTM2 with a shrunken centrum semiovale reference region and converted to DVR with a cerebellum reference region.

Result

The AD group showed significant widespread reductions in cortical and subcortical synaptic density, most pronounced in medial temporal lobe, and significantly elevated cortical amyloid in regions commonly affected by AD pathology (Figure 1). Among pooled participants (n=57), higher global amyloid burden was associated with lower synaptic density in the majority of regions. Significant negative associations between local amyloid and SV2A were also observed across the majority of cortical regions in the pooled sample (lateral temporal, prefrontal, posterior cingulate/precuneus, lateral parietal, and lateral occipital; r=‐0.29 to ‐0.48, p<0.05) with the exception of medial temporal (r=‐0.18, p=0.17), anterior cingulate (r=‐0.19, p=0.15), and pericentral (r=‐0.23, p=0.08) cortices (Figure 2). These significant associations between either global or regional amyloid and SV2A were not observed in analyses restricted to the AD group, in both an region‐ or surface‐based analysis (Figure 3).

Conclusion

Using [11C]UCB‐J PET, widespread reductions of synaptic density were observed in AD participants. Cortical regions associated with the least accumulation of fibrillar amyloid (medial temporal lobe) were associated with the most pronounced reductions in synaptic density. Significant negative associations between both global and local amyloid and synaptic density in the pooled sample were driven by group differences, and not significant within the AD group alone. Our findings are consistent with postmortem studies describing the patterns of fibrillar amyloid burden and synaptic loss in AD.
Patient engagement in research on dementia: Perceptions from researchers in a multidisciplinary research consortium
Authors: Bethell Jennifer , Chertkow Howard , Sivananthan Saskia , McGilton Katherine S
Published: December 2020

Background

Patient ‘engagement’ or ‘involvement’ in health research refers to including people with lived experience (i.e. individuals with personal experience of a health issue and their friends, family and caregivers) in the research process – not as study subjects, but as collaborators in planning, conducting and communicating research. Patient engagement is being advanced by researchers, funding organisations, advocacy groups and others on both moral and methodological grounds. Although patient engagement in research on dementia is not new, it is becoming more common. Still, there are unresolved questions of how to incorporate, evaluate and adapt engagement activities for different types of research.

Method

We are reporting results of a survey of researchers who are members of the Canadian Consortium on Neurodegeneration in Aging (CCNA), conducted to understand their perceptions of engaging people with lived experience of dementia in research.

Result

There were 84 responses (27% response rate). Respondents included biomedical (n=10; 12%), clinical (n=35; 42%), health services (n=27; 32%) and social/cultural/environmental/population health (n=12; 14%) researchers. Overall, almost all (n=78; 93%) agreed that people with lived experience of dementia can contribute meaningfully to the research process. Nearly two thirds of respondents (n=54; 64%) indicated their research already included engagement activities and the most frequently reported motivations were to increase the quality and relevance of the research and empower people who have lived experience of dementia. They reported engagement activities took place most often in the context of knowledge translation, priority setting and study recruitment. Of those who indicated no current engagement activities (n=30; 36%), most were interested in opportunities for engagement and, for those who were not interested, the most common reason reported was that it was not relevant to their area of research. Limitations to these results include the low response rate that likely introduced some selection bias; researchers with an interest in engagement may have been more likely to respond.

Conclusion

Many CCNA researchers working in the area of dementia are engaging people with lived experience in their research. These data will be used to describe how researcher knowledge, attitudes and activities differ according to type of research.
Glyphosate‐based herbicide alters brain amino acid metabolism without affecting blood‐brain barrier integrity
Authors: Limberger Christian , Ferreira Pamela C.L. , Fontella Fernanda U. , Oliveira Ana Cristina Laydner Joly , Salles Giovanna Bortoluzzi , Souza Diogo O. , Zimmer Eduardo R. , de Souza Débora Guerini
Published: December 2020

Background

Glyphosate‐based herbicides (GBH) are the most widely used pesticides, mainly due to their use in genetically modified crops. Lately, GBH induced‐neurotoxic effects are gaining attention since they are potential risk factors for developing neurodegenerative diseases, including Alzheimer’s disease (AD). It has been shown that GBH exposure is associated to brain glutamatergic excitotoxicity ‐ a key pathological feature in AD, which may cause blood‐brain barrier (BBB) breakdown. In addition, the activity of some urea cycle enzymes and arginine downstream metabolites seem to be altered in AD patient brains. Based on that, we aimed at evaluating central and peripheral effects of GBH acute exposure.

Method

GBH was administered into adult male Wistar rats (90 day‐old, n = 14) in a single oral dose (400 mg/kg). The AA and albumin levels in CSF were assessed by High‐Performance Liquid Chromatography in control conditions and 3, 24 and 48 h after administration. Serum urea content was measured by colorimetric assay. L‐[3H]glutamate uptake and AA release were measured in tissue slices of parietal cortex, hippocampus and striatum to better understand alterations in 3 h (n = 8).

Result

CSF levels of excitatory AA aspartate and glutamate, as well as ornithine ‐ a downstream arginine metabolite ‐ were elevated 3 h after GBH exposure (Figures 1A, 1D). Accordingly, high levels of ornithine were released from slices of all brain regions in the same time point (Figure 1B). We did not observe changes in serum urea, CSF albumin levels (Figure 1C) and L‐[3H]glutamate uptake.

Conclusion

We hypothesize that GBH directly affects brain AA metabolism regardless of its effects in the periphery, since we observed changes in CSF AA levels independently of BBB breakdown. Additionally, no changes in serum urea were observed, which points to a normal function of the urea cycle and a higher production/release of ornithine from brain cells. This suggests a potential unbalance in excitatory amino acids and arginine downstream metabolism as an effect of GBH exposure, which could contribute to GBH‐induced neurotoxicity. This work is in progress and we intend to characterize GBH long‐term exposure effects and its possible contribution to the pathogenesis and/or progression of AD.
Virtual navigation and scene exploration in early Alzheimer's disease
Authors: Parizkova Martina , Kalinova Jana , Vyhnalek Martin , Hort Jakub , Wiener Jan , Laczó Jan
Published: December 2020

Background

Spatial navigation deficits are present early in Alzheimer´s disease (AD) and could thus serve as an early cognitive marker of the disease. AD patients were shown to have altered scene exploration during spatial navigation as they overlook objects of interest. We aimed to evaluate the potential of a virtual spatial navigation task and eye‐tracking assessment to identify individuals with early AD and to differentiate them from those with cognitive deficit of other etiology.

Methods

48 participants: amnestic mild cognitive impairment (aMCI) with positive AD‐biomarkers (aMCI due to AD, n=14), aMCI with negative biomarkers (aMCI AD‐negative, n=8), mild AD dementia (n=9) and cognitively normal (CN) older adults (n=17) underwent clinical and neuropsychological evaluation, MRI brain scan, amyloid PET imaging, cerebrospinal fluid biomarker assessment and spatial navigation testing in a virtual realistic‐looking “Intersections” test. The test consisted of three tasks: i) egocentric “route repetition”, where participants repeated the route through a virtual city, ii) allocentric “route retracing”, where participants indicated their way back, and iii) allocentric “different approach direction” combined with eye‐tracking, where participants indicated their original position from a different perspective at each intersection with two same and two unique houses. Number of fixations and length of fixation of unique houses were analyzed.

Results

The aMCI due to AD and mild AD dementia groups had lower scores in the egocentric “route repetition” and allocentric “route retracing” tasks compared to the CN (p<0.012) and aMCI AD‐negative (p<0.007) groups. There were no differences between the CN and aMCI AD‐negative groups in these tasks. The AD dementia group had lower scores in the allocentric “different approach direction” task compared to the CN group (p=0.027). Duration and number of fixations of unique landmarks in the “different approach direction” was similar across all groups that demonstrated higher number and longer duration of fixations regardless of the task performance (p<0.001).

Conclusion

The egocentric and allocentric tasks from the virtual “Intersection” test reliably detect spatial navigation impairment typical for early stages of AD. Spatial navigation unlike scene exploration can differentiate individuals with aMCI due to AD from those with non‐AD etiology.
Associations between subjective cognitive decline (SCD) diagnosis and severity with plasma tau and NfL levels using SIMOA technology
Authors: Azad Dishari Zaman , Debure Ludovic , Vedvyas Alok , Osorio Ricardo S , Masurkar Arjun V , Wisniewski Thomas , Shao Yongzhao
Published: December 2020

Background

Subjective cognitive decline (SCD) is thought to be a preclinical stage of Alzheimer’s disease (AD) and is based largely on subjective report data in the context of normal neuropsychological functioning. There is, however, an unclear relationship between SCD and potential plasma markers along the AD spectrum.

Method

213 older adults (53 cognitively normal, [NL], 52 SCD, 54 mild cognitive impairment [MCI] and 54 AD), mean age 74.9±9.6, completed the UDS 3.0 battery, the Global Deterioration Scale (GDS) and a blood draw. Plasma levels of Aβ40, Aβ42, neurofilament light (NfL) and tau were measured using ultra‐sensitive, single‐molecule array (SIMOA) technology.

Result

Plasma NfL levels were high in MCI patients and higher still in those with AD over cognitively unimpaired people (NL and SCD) (F(2,198)=22, p<.001) before and after correction for age, sex and apoE4 status. Both plasma tau and Aβ42 levels were higher in SCD over NL subjects (F(1,95)=7.8 and F(1,96)=6.5; both p<0.05). Importantly, plasma tau but not Aβ42, Aβ42/ Aβ40 ratio or NfL was correlated with self‐reported Cognitive Change Index (CCI) scores both in the overall sample (r154=2.4, p<0.01) and in the NL and SCD only (r89=2.15, p<0.5).

Conclusion

Plasma NfL is a potential biomarker of cognitive decline to MCI and AD, while plasma tau may have higher discriminatory value in the preclinical stages of the disease and is associated with SCD.
Association of depression and diabetes mellitus with processing speed, inhibitory control and cognitive flexibility in older adults with mild cognitive impairment
Authors: Costa Mônica Vieira , de Paula Jonas Jardim , Ávila Rafaela , Pires Lívia Rabelo , Cintra Marco Túlio , Dias Raphael Figueiredo , Bicalho Maria Aparecida
Published: December 2020

Background

Depression and diabetes mellitus (DM) are associated with an increased risk for dementia and mild cognitive impairment (MCI). Subcortical anatomical changes associated with processing speed impairment are shared by both DM subtypes. This profile is similar for depression, a condition in which processing speed and executive functions mediate deficits in other domains. Thus, the aim of this work is to investigate the interaction between diabetes and depression with executive functions and processing speed on older adults with mild cognitive impairment.

Method

76 elderly people aged 60 to 96 years (M=75, SD=7.5) from UFMG outpatient clinic for older adults on Instituto Jenny de Andrade Faria participated in the study, predominantly low formal education (M=4, SD=4.5), 23 with significative depressive symptoms, 21 with diabetes mellitus, and 7 with both conditions. Multivariate analysis of variance was used (with cognitive variables as dependent, depression and diabetes as factors and age and education as covariates). Statistical method used was GLM and post‐hoc LSD analysis (Fisher's least significant difference). The level of significance adopted was 0.05. Processing speed, inhibitory control and cognitive flexibility were the study dependent variables, measured by the Five Digit Test.

Result

Diabetes is associated with processing speed impairment (F =5,505; p =0,022; partial η2 = 0,073) and depression symptoms with decrease in inhibitory control (F =6,467; p =0,013; partial η2 = 0,085). The interaction between two conditions is associated with poorer performance in inhibitory control (F =6,423; p =0,014; partial η2 = 0,084).

Conclusion

Subcortical anatomical changes associated with processing speed impairment are shared by depression and diabetes mellitus. But when two conditions are compared on a similar group of older adults with mild cognitive impairment, executive functions decline is more expressive than processing speed on patients with depression. These results corroborate those found in the literature, where the cognitive decline in patients with depression is mediated by executive functions and on diabetes by processing speed.
Obstructive sleep apnea is associated with depressive symptoms among patients with mild cognitive impairment
Authors: Chou Mei‐Chuan , Chen Shiou‐Lan , Hsu Chung‐Yao , Ke Liang‐Yin , Tsai Ming‐Hsien , Chen Sharon Chia‐Ju , Chen Chu‐Huang , Lai Chiou‐Lian , Liu Ching‐Kuan
Published: December 2020

Background

Obstructive sleep apnea (OSA) is increasingly recognized as a modifiable risk factor of cognitive decline and dementia. However, the impacts of OSA on mood among patients with mild cognitive impairment (MCI) have remained rarely explored. The aim of this study was to investigate whether OSA is associated with depressive symptoms among patients with MCI.

Method

The diagnosis of MCI was based on the criteria proposed by Peterson in 2004 after a series of comprehensive work‐up. The over‐night polysomnography (PSG) was performed in hospital for the diagnosis of OSA and the patients with AHI of 10/hour or higher were eligible for enrollment in the OSA group. The group for comparison was composed of the patients without OSA (AHI < 5/hour) by over‐night PSG and the patients with low risk of OSA defined by Berlin Questionnaire. The Center for Epidemiologic Studies Depression Scale (CESD) was administered for assessing depressive symptoms and the Cognitive Abilities Screening Instrument (CASI) with derived Mini‐Mental State Examination (MMSE) score was used for assessing cognitive function. Apolipoprotein E (APOE) genotyping was done in each subject.

Result

The study sample was composed of 68 MCI patients (age: 67.5 ± 8.83 years; female: 46.8%). As compared to the MCI patients without OSA or with low risk of OSA (n=14), the MCI patients with OSA (AHI ≥ 10/ hour; n=54) had higher CESD score ( 15.8 ± 10.6 versus 7.1 ± 1.9 ; P = 0.011). In the multivariate analysis, the association remained significant after adjusting the confounding factors including age, gender, education years, baseline CASI score, BMI and APOE epsilon 4 genotyping status. (β = 5.54; 95 % CI: 0.63– 10.45, p = 0.028).

Conclusion

The results of this cross‐sectional study suggest that obstructive sleep apnea is independently associated with depressive symptoms among patients with MCI. The long‐term effects of OSA on the mood among MCI patients warrant longitudinal studies. Our results probably set the horizon for the basic researches for the delineation of pathological mechanisms underlying the association between OSA and depression among MCI patients.
The status of digital pathology and machine learning within Alzheimer’s Disease Centers
Authors: Dugger Brittany N. , White Charles , Stahly Brian , Schneider Julie A. , Robichaud Elizabeth , Reichard Ross R. , Prokop Stefan , Perrin Richard J. , Nelson Peter T. , Lieberman Andrew P. , Kukull Walter A. , Kofler Julia , Keene C. Dirk , Kapasi Alifiya , Irwin David J. , Flanagan Margaret E. , Crary John F. , Chan Kwun Chuen Gary , Murray Melissa E. ,   The Alzheimer's Disease Center Digital Pathology Working Group
Published: December 2020

Background

Digital pathology and machine learning (ML) workflows have paradigm shifting potential especially in the field of Alzheimer’s disease and related disorders. However, many institutions/centers may not have access to these technologies. To provide benchmark data, a survey was developed and distributed to National Institutes of Health’s Alzheimer’s Disease Centers (ADCs) in the United States.

Method

Survey questions covered topics such as: infrastructure (i.e. type of digital slide scanners used), funding sources (i.e. how the scanner was funded), and data management/storage (i.e. size of digital files). After development, review, and approval by the ADC digital pathology working group, the survey was distributed via email to 35 past and current ADC directors and/or ADC neuropathology core leaders. Participation in the survey was completely voluntary and answers did not contain any personal data.

Result

The survey generated over a 90% response rate, and the majority of those who completed the survey were neuropathology core leaders; 81% stated their ADC had access to a digital slide scanner, most common brand being Aperio/Leica. One third of respondents stated there was a fee for service to utilize the scanner. For digital pathology and/or ML resources, 40% of respondents stated none are supported in any way by their ADC. To cover the purchase and operation of the scanner, 50% stated they had institutional support. Many were unsure of the approximate average scanned file size of digital images (37%) and total amount of storage space that files occupied (50%). Many (75%) were aware of other departments at their institution working with digital pathology and/or ML, but a similar percentage was unaware of multi‐university or industry partnerships.

Conclusion

These results demonstrate many ADCs have access to a digital slide scanner and had institutional support to cover the purchase. However, further investigation is needed to understand hurdles and barriers for implementing both digital pathology and ML workflows aiding in standardized methods across ADCs.
Monitoring disease pathophysiology longitudinally using multiparametric PET acquisitions: The McGill TRIAD cohort
Authors: Stevenson Jenna , Chamoun Mira , Benedet Andréa Lessa , Rahmouni Nesrine , Gagné Guylaine , Savard Mélissa , Cellucci Tasha Vinet , Poltronetti Nina Margherita , Pascoal Tharick A. , Lussier Firoza Z. , Tissot Cécile , Therriault Joseph , Stevenson Alyssa , Vitali Paolo , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2020

Background

The Translational Biomarkers in Aging and Dementia (TRIAD) cohort aims at describing the biomarker trajectories and interactions between pathophysiological processes as drivers of dementia. While focusing on advanced personalized and preclinical dementia diagnosis, TRIAD’s main objectives include understanding the interactions between amyloid‐β and tau and their role in the progression of brain atrophy and cognitive decline; as well as the role of neuroinflammation, epigenetics and synaptic depletion as mediators of cognitive decline.

Method

Inclusion into the TRIAD cohort begins with a telephone screening ensuring the participant’s eligibility. Participants sign an ethically approved consent form where they agree to donate biofluids (blood, urine, saliva and cerebrospinal fluid) at the first on‐site visit. The second visit consists of an extensive neuropsychological battery, followed by PET and MRI visits. The PET scans completed are dependent on their diagnosis and the project in which they are enrolled. TRIAD cohort uses a variety of tracers in their different projects to detect the presence of different protein accumulation in the brain. These tracers include [18F]MK6240, [18F]AZD4694, [18F]AV1451, [18F]PI2620 and [18F]RO948, [11C]PBR28 or [18F]DPA, [18F]FEOBV [11C]MRT and [18F]SDM‐8. TRIAD participants complete intermediate telephone follow‐up calls at 6 and 18 months and return for follow‐up clinical and imagery visits 12 and 24 months after baseline, with a retention rate of 75%.

Result

Since 2017, the TRIAD registry has recruited 1,285 people and enrolled 576 participants. Enrolled in the TRIAD studies are individuals without cognitive impairment (n=345), with mild cognitive impairment (n=75), sporadic and autosomal‐dominant Alzheimer’s disease (n=90), atypical dementia (n=27) and individuals under evaluation (n=39). The TRIAD cohort currently banks 495 baseline blood collections and 108 follow‐up collections with 85 participants having completed 12‐month follow‐up scans and neuropsychological evaluation.

Conclusion

With a strong participant retention rate, TRIAD presents a striking opportunity to further understand the progression of Alzheimer’s disease with resources ready to uphold the use of affordable biomarkers, capable of diagnosing and measuring disease progression.
Defining longitudinal change on the auditory verbal learning test using a conditional normative model to account for practice effects: Preliminary validation in preclinical Alzheimer’s disease
Authors: Alden Eva , Lundt Emily S. , Christianson Teresa J. , Machulda Mary M. , Kremers Walter K. , Jack Clifford R. , Knopman David S. , Petersen Ronald C. , Mielke Michelle M. , Stricker Nikki H.
Published: December 2020

Background

Practice effects can obscure interpretation of longitudinal cognitive performance. Reliable change indices (RCIs) provide data for determining a significant change, typically for a single repeat assessment, but multiple follow‐up visits are common clinically and in research cohorts. Further, regression‐based or linear mixed effects models improve prediction of future cognitive decline and have higher correlations with neuroimaging biomarkers than RCI approaches. We present norms for change for the Auditory Verbal Learning Tests (AVLT) with conditional normative z‐scores for up to 7 repeat assessments, and demonstrate application of this method to individuals with preclinical Alzheimer’s disease (AD).

Method

Normative Sample: Robust conditional norms were derived from 1001 adults ages 50‐90 from the Mayo Clinic Study of Aging (MCSA) who completed the AVLT across 4‐8 visits approximately 15 months apart and remained cognitively unimpaired (CU) across all available visits. Linear mixed effects models were used to compute a conditional normative z‐score for AVLT 30‐minute recall and sum of trials. Models included adjustment for baseline performance, number of prior test exposures, demographic factors (age, sex, education), and interactions (baseline*time; sex*time). Test Sample: We used a preclinical AD sample with positive amyloid and tau imaging (n= 27 CU A+T+; Jack et al. 2017) expected to have a higher rate of intra‐individual cognitive decline relative to CU A‐T‐ individuals (n = 268) to compare mean performances of conditional normative z‐scores to typical age‐corrected Mayo’s Older Americans Normative Studies (MOANS) norms. Participants had at least 1 and up to 4 follow‐up visits, with their most recent AT data used for classification.

Result

AVLT performance based on typical norms did not differ across A+T+ and A‐T‐ groups. Specifically, across 2‐4 follow‐up visits, the typical norms mean z‐score was similar across groups (p=0.945; see Table 1). However, the conditional norms mean z‐score that accounts for practice effects and typical trajectories of AVLT performance was lower in the A+T+ relative to the A‐T‐ group for 30‐minute recall (p=0.055) and sum of trials (p=0.060).

Conclusion

Conditional normative methods that account for practice effects are more sensitive to preclinical AD than typical norms, and show promise for identifying transitional cognitive decline.
Association of the cognitive‐motor syndrome with the incidence of dementia
Authors: Vargas Anamaria Rosales , Acosta‐Castillo Gilberto Isaac , Sosa‐Ortiz Ana Luisa
Published: December 2020

Background

The cognitive‐motor syndrome (CMS) describes the association of cognitive and gait alterations, being potentially useful for predicting dementia. The criteria proposed for the CMS are: cognitive complaint, decrease in gait speed, preservation of daily life activities, and absence of dementia.

Method

This work is a population‐based cohort secondary analysis. We studied 1,823 adults older than 65 years, without dementia at the baseline evaluation. The follow‐up evaluation was done after three years. We first estimated the association of the CMS with sociodemographic and clinical variables, followed for the dementia incidence, using a cumulative incidence reasons model.

Result

The incidence of dementia cases was associated with the following sociodemographic variables: age, education level, and the number of assets and services at home. Regarding the clinical variables analyzed, we found that the incidence of dementia was associated with diabetes mellitus and depression.

According to the cumulative incidence ratios, the patients that presented the cognitive‐motor syndrome have a risk ratio of 1.69 (95% CI: 0.68‐419) for developing dementia (p = 0.25).

Conclusion

According to the criteria used in this analysis, we did not find an association between the CMS and the incidence of dementia. One limitation to consider in our study is the short follow up period and the low prevalence of CMS opposite to other epidemiological studies that describe a prevalence of up to 7% with n = 997 (Verghese et al., 2013). We propose to explore new alternatives for the operationalization of this syndrome since the CMS has emerged as a robust short‐term predictor for the development of dementia.
The impact of hearing loss on cognitive decline and risk of progression to mild cognitive impairment in healthy adults
Authors: Bucholc Magda , McClean Paula , Bauermeister Sarah D.
Published: December 2020

Background

Hearing loss is the third most commonly reported chronic disease in older adults. Its prevalence ranges from 30% in individuals aged 65‐74 years to 40%‐60% in those aged 75 years or older. Evidence suggests that age‐related hearing impairment is strongly and independently associated with the decline in cognitive abilities and that individuals with hearing loss develop cognitive decline earlier than people with normal hearing. In this study, we used data from a large referral‐based cohort to investigate the effect of hearing impairment on cognitive decline and progression to mild cognitive impairment (MCI) in healthy adults.

Method

The longitudinal National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS), consisting of observations from the period 2005‐2018, was used to assess the impact of hearing loss on cognition and conversion to MCI in cognitively healthy individuals. The incidence of MCI was determined based on the clinical diagnosis. The analytic sample for this study included 691 participants (age >40) with hearing impairment. Kaplan‐Meier survival functions were used to estimate the distribution of survival times for patient subpopulations i.e. patients with and without hearing impairment. The survival duration was defined as the number of years between the baseline ‘healthy’ diagnosis and the first MCI diagnosis during the follow‐up. Cox proportional hazards regression model was developed to study time to incident MCI. Sensitivity analysis was performed to control for confounding.

Result

Patients diagnosed with hearing impairment were at substantially higher risk of converting to MCI (hazard ratio [HR] 1.3; 95%CI, 1.07‐1.55; p = 0.008). Kaplan‐Meier analysis for the cumulative risk of MCI revealed large differences in survival rates by hearing impairment status (p = 0.0003). Sensitivity analysis confirmed the robustness of our findings. The results obtained after prosperity score matching again showed a significant association between hearing impairment and risk of conversion to MCI (HR 1.43; 95%CI, 1.14‐1.80; p = 0.002).

Conclusion

We demonstrated the impact of hearing loss on cognition of healthy individuals. Future work will focus on evaluating the relationship between the use of hearing aids and conversion to MCI in hearing‐impaired healthy adults as well as investigating the mechanistic basis of this association.
Neuropsychological profile of language alterations in subcortical dementia of the white and gray matter
Authors: de Lacerda Maria Carolina Cabral , Caixeta Leonardo Ferreira
Published: December 2020

Background

In the twentieth century, it was believed that the injury cortical was the substrate of cerebral dysfunction neuropathological. Studies of dementia were primarily focused on disorders of the cerebral cortex and sub cortical gray region, which originated the concepts of cortical and subcortical dementia respectively. The report of dementia mainly involving the white brain received less attention.

Method

15 patients were evaluated with DSB, 8 with DSC and 14 control subjects. We applied the following tests: Boston for Diagnostic of Aphasia Examination (BDAE), the Boston Naming Test (BNT), Token Test, Verbal fluency ‐ semantic category and board Theft of biscuits.

Result

The results showed that the subcortical group showed worse performance with the control group, showing significant differences in the Boston Naming Test and on the evidence of comprehension and oral production and graphics for the Boston Diagnostic Test of Aphasia. The DSB group showed more significant changes when compared with the control group than in the comparison between DSC X control group. Despite the language is related to cortical involvement, our study showed that such changes are found in subcortical dementia and receiving influence of cognitive processes involved in language. Symptoms of changes in language were similar between groups subcortical, but in greater or lesser degree of commitment. The DSB group showed more impairment of comprehension and oral apraxia and DSC group is highlighted by changes in prosody and the presence of hyperkinetic dysarthria.

Conclusion

The subcortical groups showed greater language impairment than the control group, formed by patients with cortical dementia and the domains most seriously involved were those of complex ideational understanding, oral and graphic speech, naming and apraxia, also another symptom present exclusively in this group.
Circulating extracellular vesicles as an emerging tool for the early detection of Alzheimer’s disease or other dementia
Authors: Khedher Mohamed Raâfet Ben , Haddad Mohamed , Laurin Danielle , Ramassamy Charles
Published: December 2020

Background

Alzheimer disease (AD) and vascular dementia (VaD) are the most common form of dementia worldwide. Actually, the search for early peripheral biomarkers for AD and other dementia represent a great challenge. Exosomes or extracellular vesicles (EVs) are key players in cerebral function. We have demonstrated that the levels of some pathogenic proteins related to AD (amyloid, Tau..) were higher in circulating EVs (pEVs) than in plasma with a differential regulation in controls, mild cognitive impairment (MCI) and AD patients. However, it is not clear whether these changes are specific to AD or other dementia subtypes. Our prospective study aims to identify, in pEVs and in plasma, early specific biomarkers in pre‐clinical cognitively impaired non demented patients (CIND) that develop different types of dementia.

Method

pEVs were isolated from plasma of healthy volunteers, AD patients and CIND patients stratified according to the type of dementia these patients develop five years after as follows: CIND, CIND‐AD, CIND‐VaD and CIND‐mixed dementia. EVs were characterized by NTA analysis, transmission electron microscopy and western‐blot measurement of vesicular proteins such as TSG101 and CD63. The selected brain‐specific proteins were assessed by Luminex assay.

Result

Our results showed that pEVs display a better discriminating capacity than plasma for most of the studied proteins. DJ‐1 and NSE concentration in EVs were increased in CIND‐VaD patients but not in CIND‐AD suggesting their utility as early markers for VaD. The levels of ANGPTL‐4, lipocalin and α‐synuclein in pEVs were able to discriminate specifically the apparent‐stages of AD. The α‐synuclein/DJ‐1 ratio measured in pEVs was reduced in all groups and could not provide a fair classification of dementia subtypes. In addition, the levels of APP, MMP‐9, progranulin S100B and pentraxin‐2 were unchanged in pEVs and plasma.

Conclusion

The present work show that several proteins contained in pEVs are differently expressed depending on the type of dementia and prompt the use of pEVs in early dementia diagnosis. This work was supported by the Chaire Louise & André on Alzheimer’s disease, Foundation Armand‐Frappier (CR) and CIHR grant (TF).
Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease
Authors: Gate David , Saligrama Naresha , Levanthal Olivia , Davis Mark , Wyss‐Coray Tony
Published: December 2020

Background

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder in which neuroinflammation plays a critical function. Yet, little is known about the contribution of the adaptive immune response in AD. Here we used integrated analyses of multiple cohorts to identify peripheral and central adaptive immune changes in AD.

Method

First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of AD consisting of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells.

Result

In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single cell RNA sequencing revealed their enhanced T cell receptor (TCR) signaling. Notably, by utilizing multiple single cell TCR sequencing strategies on a third cohort, we discovered clonally expanded CD8+ TEMRA cells in patient cerebrospinal fluid (CSF). Finally, we used machine learning, cloning, and peptide screens to demonstrate specificity of clonally expanded AD CSF TCRs to two separate Epstein‐Barr virus antigens.

Conclusion

These results reveal a novel blood‐CSF adaptive immune response in AD and provide evidence of clonal, antigen‐experienced T cells patrolling the intrathecal space of brains affected by age‐related neurodegeneration.
Relation between working into old age and MMSE: A study on older dressmakers in Japan
Authors: Sooudi Kazuyo K
Published: December 2020

Background

The number of older adults in Japan with dementia including MCI is estimated to increase to 13 million by 2025. The author’s earlier study indicated that a top concern among Japanese is dementia. The government also plans to increase the age to receive pension, which means older adults must work much longer. Purpose: To identify any benefits of working beyond retirement age from a dementia point of view.

Methods

Conducted the MMSE and one‐on‐one interviews with working seniors about their beliefs and life values (n=11). Analyzed interview contents using text mining tool. Ethical considerations: Ethics Committee of Nakamura Sewing Company approved research plan.

Results

Fifty percent of subjects work full time (Av. Age: 73, 66‐80 YO. old, SD=4.1). All subjects achieved a perfect score on the MMSE, except on calculation (Av. score 2.6, 1‐5). Through text mining, top 4 words (word cloud) were “health, customer, satisfaction, responsibility” and top 3 words (word frequency) were “age, responsibility, equal.” All subjects walk to office (Av. 3km). Discussion: Although previous studies have stated that cognitive decline in memory starts in one’s late 30’s and reasoning/verbal ability in one’s 50’s, the subjects in this study did not show any obvious decline through the MMSE and the interview process. Most of them work as dressmakers an average of 30hours/w. This small study indicates that working into older age may contribute not only to financial security but also to delaying dementia. All subjects stated that they are very conscious not to use their age as an excuse for any error they make and expect to get equal remuneration for their work.

Conclusions

Active lifestyle including working into the old age may be a way for older Japanese to maintain personal health (delaying and/or avoiding dementia) and also to sustain financial security.