bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating Template Generation Methods for Spatially Normalizing Down Syndrome Brain Magnetic Resonance Images
Authors: Luo Weiquan , Minhas Davneet S , Tudorascu Dana L , Cohen Ann D , Ances Beau M , Zaman Shahid , Christian Bradley T , Klunk William E , Handen Benjamin L , Laymon Charles M
Published: December 2022

Background

Magnetic resonance (MR) image registration and segmentation algorithms commonly used in studies of neurodegeneration have a higher failure rate for Down syndrome (DS) populations due to anatomical and morphological differences. For example, the Desikan‐Killiany atlas used by FreeSurfer was defined using MR images from cognitively normal adults and patients with Alzheimer’s disease (AD). The aim of this work was to evaluate three template generation methods (or group‐wise image registration) for spatially matching DS MR images and generating a DS cohort‐specific template.

Method

138 scans of DS subjects from the NiAD consortium were employed. The three template generation methods evaluated were DARTEL, SHOOT, and SyGN. DARTEL and SHOOT are implemented in the SPM12 (v7771) software package and operate on tissue segmentation maps. SyGN is implemented in ANTs software and operates on MR images. The data processing pipeline is presented in Figure 1. Scan‐specific grey matter (GM) and white matter (WM) tissue probability maps were generated using SPM12’s Unified Segmentation method for DARTEL and SHOOT, and MR images were skull‐stripped for SyGN. To evaluate spatial matching, all MR images were warped to each template space using method‐specific deformation fields and an average MR image was generated specific to each template method. Structural similarity index measure (SSIM) and Normalized Mutual Information (NMI) metrics were calculated on a scan specific basis relative to the average MR image for each template method. Lower SSIM and NMI measures effectively reflect greater spatial variability across DS scans and therefore worse spatial matching performance.

Result

The DARTEL and SHOOT tissue map (GM and WM) templates and SyGN MR template are presented in Figure 2. Average MRs for each template method are presented in Figure 3. Consistent relationships were observed between the 3 template generation methods for the mean (SHOOT > SyGN > DARTEL) and standard deviation (SyGN < DARTEL < SHOOT) of SSIM and NMI (Figures 4 and 5, Table 1).

Conclusion

With relatively high means and the lowest standard deviation, SyGN produced robust spatial matching across all scans. Future Down syndrome MRI and PET image processing will make use of the SyGN template.
Relationship between MTA visual scale scores and hippocampal volume measured by a medicaldevice in patients from a multicentric memory clinic population
Authors: dos Santos Clarisse Longo , Cavedo Enrica , Gordon Elizabeth , Samper‐Gonzales Jorge , Schwarz Adam J. ,   MEMENTO study group
Published: December 2022

Background

The medial temporal lobe (MTL), including the hippocampus, undergoes atrophy in patients with Alzheimer's disease (AD). Visual rating of medial temporal lobe atrophy (MTA) is often performed in the assessment of patients with cognitive impairment. Calculation of hippocampal volumes (HV) can also be achieved by multiple automated and semi‐automated methods using T1‐weighted MR images. The current study investigated the relationship between HV and z‐scores calculated by an automated method, included in the QyScore® medical device, and visual MTA rating scores using Scheltens’ scale in a multicentric memory clinic population at baseline.

Method

1959 participants from the MEMENTO cohort (Age 71.02 +/‐ 8.61, 1218 Female, MMSE 27.95 +/‐ 1.91) had 3DT1 MRI scans analyzed with QyScore®, an FDA‐approved and CE‐marked image analysis software. HV are reported in mL, corrected for % Intra Cranial Volume (ICV), and in z‐scores calculated relative to a cognitively normal population. 814 had amyloid status from CSF or PET, of which 216 were Amyloid+. Correlation between MTA scores and quantitative HV measurements was ascertained by Spearman’s rank correlation.

Result

There was a significant negative correlation between MTA scores and HV in %ICV (Left ‐0.62, p<0.001; Right ‐0.59, p<0.001) and z‐scores (Left ‐0.47, p<0.001; Right ‐0.43 p<0.001) for the total sample, as well as in Amyloid+ individuals HV in %ICV (Left ‐0.63 p<0.001, Right ‐0.58 p<0.001) and z‐scores (Left ‐0.50 p<0.001, Right ‐0.47 p<0.001). The correlation was also strong when separated by clinical diagnosis: patients with Subjective Cognitive Complaint (SCC, N= 306, AGE: 69.82 +/‐ 8.03, 196 female, MMSE: 28.86 +/‐ 1.17) and MCI (N = 1646, Age: 71.23 +/‐ 8.71, 1018 Female, MMSE: 27.79 +/‐ 1.95) presented MTA scores correlated both with HV in %ICV (Right= ‐0.47 p<0.001, Left= ‐0.50 p<0.001 for SCC; Right= ‐0.60 p<0.001, Left= ‐0.63 p<0.001 for MCI) and z‐scores (Right= ‐0.26 p<0.001, Left= ‐0.33 p<0.001 for SCC; Right= 0.44 p<0.001, Left= ‐0.49 p<0.001 for MCI).

Conclusion

The automated quantification of ICV‐corrected HV and z‐scores were well‐correlated to MTA scores. QyScore® z‐scores may improve specificity in patients with cognitive impairment, by providing automated quantification of hippocampal atrophy directly compared with healthy ageing
Longitudinal CSF biomarker trajectories from middle age to late adulthood
Authors: Pettigrew Corinne , Soldan Anja , Wang Jiangxia , Wang Mei‐Cheng , Greenberg Barry , Albert Marilyn S. , Moghekar Abhay
Published: December 2022

Background

Current cerebrospinal fluid (CSF) biomarker data of preclinical AD are based largely on cross‐sectional studies across the disease spectrum and short‐term longitudinal studies, with most studies conducted among older adults. However, neuropathological studies indicate that AD pathology is present in midlife. To better understand within‐person biomarker trajectories, we examined longitudinal changes in CSF biomarkers, potential modifiers (e.g., demographics, APOE4 genotype), and changes with respect to MCI symptom onset among participants who were primarily middle‐aged and cognitively normal at baseline, and have on average 10.7y of follow‐up (max 23y).

Method

CSF was collected from 278 BIOCARD Study participants (M baseline age = 57.5y; Table 1); 94 (33.8%) have since progressed to MCI or dementia. These analyses focused on z‐transformed values of AB42/AB40, p‐tau181, and t‐tau, measured using the Fujirebio Lumipulse G1200 assays.

Result

In longitudinal mixed‐effects models, there were accelerated (quadratic) increases in p‐tau181 and t‐tau over time, and a trend for accelerated (quadratic) decreases in AB42/AB40 (p=0.09). APOE4 carriers had lower levels of AB42/AB40 at baseline and greater rates of change in all biomarkers (Table 2; Figure 1). Older participants had more abnormal baseline biomarker levels and greater rates of change in AB42/AB40 and t‐tau. Biomarker levels and trajectories were unrelated to sex and years of education. In a separate set of models, low baseline AB42/AB40 was associated with increases in p‐tau181 and t‐tau over time, whereas baseline t‐tau and p‐tau181 were not associated with change in AB42/AB40. Finally, compared to those who remained normal, those who progressed to MCI/dementia had more abnormal AB42/AB40, p‐tau181, and t‐tau at baseline, and greater rates of change in t‐tau and p‐tau prior to MCI clinical symptom onset.

Conclusion

These results indicate that, in preclinical AD, lower levels of amyloid are associated with increases in p‐tau181 and t‐tau, while accelerations in p‐tau181 and t‐tau are more closely linked to MCI symptom onset. They also suggest earlier and greater rates of pathology accumulation among APOE4 carriers, but that sex and education‐related differences in AD dementia risk are not due to differences in AD biomarker accumulation early in the disease course.
Monitoring abnormal nocturnal behaviour in the homes of patients living with dementia ¶
Authors: Soreq Eyal , Kolanko Magdalena A , Monica Ciro della , Ravindran Kiran K.G. , Revell Victoria Louise , de Villèle Paul , Barnaghi Payam , Dijk Derk‐Jan , Sharp David J ,   CRT group
Published: December 2022

Background

People living with dementia (PLWD) often exhibit marked sleep disturbances. These cause substantial care challenges and may be causally related to dementia progression. Collecting ecologically valid data on sleep disturbance in naturalistic settings has been difficult. As a result, sleep assessments in PLWD are generally limited to short studies in sleep laboratories or data collection from wearables, where compliance is problematic. Here, we demonstrate how passive internet of things (IoT) sensors can be used to monitor the effects of dementia on nocturnal behaviour and physiology.

Method

Using the Withings under‐mattress pressure sensor, we validated bed occupancy and physiological measures in 35 older adults tested both at home and in the laboratory. We then examined data collected between 2019 and 2021 from the general population (N=13,663) and from a cohort of PLWD taking part in the UK DRI study of home monitoring for PLWD (N=46). More than 4 million unique bed mat observations were analysed.

Result

Arise time across all subjects was negatively correlated with time to bed (Fig.1a, r(13,617)=‐0.5, p<.0001). Bed occupancy increased with age, but PLWD spent more time in bed than age‐matched controls (Fig.1b) and had more nocturnal awakenings (Fig.1c). Explainable gradient boosting machine learning was successfully used to classify data from individual nights (PLWD vs. general population). PLWD probability was related to specific changes, such as increased awakenings, high or low time spent in bed, high heart rate and low breathing rate (Fig.2). We also explored variations in night‐time behaviour and physiology over time for individual PLWD (Fig.3a). High within‐subject variability was present, which related to disease progression, intercurrent illness and changes in medication. Data from each night was transformed into a risk score for each metric (Fig.3b) and a compound risk score. These quantify the risk of abnormal night‐time behaviour and physiology produced by dementia (Fig.3c) and reflect clinically relevant changes in PLWD.

Conclusion

Taken together our work demonstrates how digital biomarkers collected passively using under mattress technology can be used to automatically monitor the nocturnal effects of dementia across large populations. The approach is also potentially applicable for preclinical screening and the evaluation of treatments effects.
Brain TSPO expression is associated with plasma pTau181 & pTau231 across the AD spectrum
Authors: Rahmouni Nesrine , Therriault Joseph , Tissot Cécile , Lussier Firoza Z , Stevenson Jenna , Stevenson Alyssa , Servaes Stijn , Ashton Nicholas J. , Kvartsberg Hlin , Arias Jaime Fernandez , Wang Yi‐Ting , Kang Min Su , Gauthier Serge , Pascoal Tharick A , Zetterberg Henrik , Blennow Kaj , Benedet Andréa Lessa , Rosa‐Neto Pedro
Published: December 2022

Background

Microglial activation is an important component of the immune response in the brain of AD patients and has been shown to follow a similar propagation pattern to tau tangle accumulation. However, it is unclear to what extent cerebral microglial activation is associated with biofluid concentrations of phosphorylated tau (pTau). The objective was to investigate whether concentrations of pTau181 and pTau231 are correlated with microglial activation indexed by [11C]PBR28 PET across the AD spectrum.

Method

The present study was conducted in a population of 130 individuals from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort: 20 young cognitively unimpaired, 65 cognitively unimpaired elderlies, 31 with mild cognitive impairment and 14 with AD dementia. Participants were evaluated with blood biomarkers and [11C]PBR28 PET. Plasma pTau181 and pTau231 concentrations were quantified using a Simoa assay. Microglial activation was assessed via [11C]PBR28 PET, standardized uptake value ratios (SUVRs) were calculated between 0 and 90 minutes post‐injection, using cerebellum grey matter as the reference region. Voxel‐based regression models evaluated the relationship between plasma pTau181 and pTau231 with neuroinflammation as assessed by PET, correcting for age and sex.

Result

In the present study, positive correlations were found between concentrations of both pTau181 and pTau231 and neuroinflammation indexed by PET‐imaging. Voxel‐level analyses indicated that these associations prenominated in regions of the default mode network including the precuneus, posterior cingulate cortex and medial prefrontal cortex. These regional associations survived corrections for multiple comparisons.

Conclusion

Peripheral phosphorylated tau is associated with neuroinflammation in brain regions associated with AD. Our findings highlight the importance of neuroinflammation in the pathogenesis of AD.
Consensus automatic speech recognition (CASR) in the California Cognitive Assessment Battery (CCAB)
Authors: Woods David L. , Hall Kathleen , Williams Garrett , Baldo Juliana , Johnson David K , Chok Jas M. , Sucich Gabriel , Pebler Peter , Blank Michael , Geraci Kristi , Herron Tim
Published: December 2022

Background

Recent reports have investigated the use of automatic speech recognition (ASR) to analyze and score verbal responses in cognitive tests. ASR scoring is objective, permits the efficient computerized administration of verbal tests, and generates timestamps that enable the detailed temporal analysis of responses. However, ASR transcription accuracy varies by engine, task, and participant, and ASR can incorrectly score responses from participants with atypical speech patterns. Here we describe the speech‐transcription pipeline of the California Cognitive Assessment Battery (CCAB), which incorporates consensus ASR (CASR) to produce more accurate transcripts than possible with any single ASR engine. We also developed a Transcript Review Tool (TRT) which facilitates the manual correction of mis‐transcribed words in problem subjects.

Method

Figure 1 shows the CCAB speech transcription pipeline. Realtime ASR transcriptions are obtained along with the transcriptions of the digital recordings of responses using six cloud‐based ASR engines (e.g., Google, etc.). Individual transcripts are then combined to produce a “consensus” transcript, and a transcription confidence measure based primarily on the agreement between ASR engines (Figure 2). If needed, “consensus” transcripts can be manually corrected using the Transcript Review Tool which enables the review of all words or just those words below a predefined CASR confidence threshold (Figure 3).

Result

ASR transcriptions were obtained from 442 healthy adults (mean age = 65.1 ±14.4) who each underwent three days of cognitive testing that included 25 verbal tests. In all, approximately 276 hours of speech were transcribed. Preliminary analyses show that CASR transcription accuracy surpassed 99% for tests with limited response sets (e.g., digit span, verbal list learning, face‐name binding, etc.) and exceeded 95% for discursive speech tests (e.g., picture description and logical memory).

Conclusion

CASR transcription is more accurate than that of any single ASR engine. When combined with the TRT, “consensus” ASR can produce error‐free, timestamped transcripts that enable the detailed analysis of verbal responses from older individuals at risk of cognitive decline.
Smartphone‐based long‐term delayed memory performance is associated with the Preclinical Alzheimer’s Cognitive Composite and CSF levels of β‐amyloid
Authors: Öhman Fredrik , Berron David , Skoog Johan , Bodin Timothy Hadarsson , Kern Silke , Zettergren Anna , Papp Kathryn V. , Zetterberg Henrik , Blennow Kaj , Skoog Ingmar , Schöll Michael
Published: December 2022

Background

Remote and unsupervised cognitive testing using smartphones may improve sensitivity to detect preclinical Alzheimer’s disease (AD). In particular, cognitive testing at‐home enables the evaluation of the potentially more sensitive long‐term delayed memory retrieval, which is commonly not feasible in a clinical setting.

Method

Here, we investigated the association between remote and unsupervised smartphone‐based cognitive assessments and in‐clinic cognitive measurement in older participants (CDR = 0, MMSE = 29.2, age = 77). The sample (non‐demented at age 70) was derived from the Swedish population‐based Gothenburg H70 Birth Cohort Studies. In a subsample of participants, the retrospective correlation with cerebrospinal fluid (CSF) biomarkers analyzed at age 70 was further explored. To this point, 177 H70‐participants have consented and were enrolled into the smartphone sub‐study. They completed an “Object‐in‐Room Recall Test“ (ORR) remotely and unsupervised using own mobile devices, and the recall session was initiated 24 hours after the initial learning phase. Available previously assessed CSF measures included the Aβ42/Aβ40‐ratio, t‐tau, p‐tau, neurofilament light (NFL), and neurogranin, available in‐clinic cognitive tests included the Rey Auditory Verbal Learning Test (RAVLT), Semantic Fluency, Digit‐Symbol‐Coding, and Mini Mental State Examination. The above‐mentioned cognitive tests were used to derive the Preclinical Alzheimer’s Cognitive Composite (PACC5), a composite designed to be sensitive to cognitive change in preclinical AD. All associations were examined using Pearson correlation coefficient.

Result

Preliminary analyses in a subset of participants yielded relatively strong positive correlations between PACC5 (R = .50, p<.001) and the ORR Long‐term Delayed Retrieval. The strongest correlation for an individual test was observed between the RAVLT Delayed Retrieval and the ORR Long‐term Delayed Retrieval (R = .52, p<.001). Regarding the CSF biomarkers, Aβ42/Aβ40‐ratio at age 70 was positively correlated with the ORR Long‐term Delayed Retrieval at age 77 (R = .43, p<.01), while measures of t‐tau, p‐tau, NFL, and neurogranin at age 70 were not.

Conclusion

Our findings demonstrate the potential of smartphone‐based cognitive assessment to detect features of preclinical AD in a population‐based sample of older adults. Future analyses will address the relationship between these novel cognitive measures in relation to longitudinal CSF‐ and neuroimaging‐based biomarkers and clinical progression.
Actigraphy and sleep‐monitoring devices to help differentiate dementia with Lewy bodies from Alzheimer’s disease
Authors: Brown Karl , Shutes‐David Andrew , Payne Sarah , Jankowski Adrienne , Seto Edmund , Wilson Katie , Tsuang Debby W
Published: December 2022

Background

Dementia with Lewy bodies (DLB) is difficult to differentiate from Alzheimer’s disease (AD) in clinical settings. Actigraphy and sleep‐monitoring devices have the potential to generate data in between clinic visits to help improve the identification of DLB.

Objective

We will assess the feasibility of measuring activity and sleep, including day/night reversal, in participants with DLB (n=5) and AD (n=4).

Method

Participants were asked to wear actigraphy devices on their wrists for 2 weeks and sleep‐monitoring EEG devices on their foreheads for 2 nights. Actigraphy recording errors were detected by logging instances in which the majority of acceleration values approached the maximum; reliability was evaluated by logging 15‐minute actigraphy and 1‐hour sleep‐monitoring periods with at least some valid data. Actigraphy tolerability was evaluated by examining non‐wear times. Ten variables were selected to evaluate day/night reversal.

Result

Averaged across all individuals, only 0.02% of the 15‐minute actigraphy recording periods had a recording error, 100% of the 15‐minute periods had at least some valid data, and only 0.15% of the periods reflected non‐wear times. For the sleep‐monitoring device, an average of 78% of each nightly recording were considered valid. Of the ten day/night reversal variables, two sleep‐monitor variables showed the strongest differences between DLB and AD: sleep efficiency (mean [SD] = 0.56 [0.19] for DLB; mean [SD] = 0.74 [0.11] for AD; see Fig. 1) and percent sleep in REM (mean [SD] = 6.83 [9.16] for DLB; mean [SD] = 18.3 [4.13] for AD; see Fig. 2). The ratio of nighttime to daytime activity as measured by actigraphy (mean [SD] = 0.37 [0.18] for DLB; mean [SD] = 0.38 [0.08] for AD) showed strong differences in the variability of measurements between AD and DLB (see Fig. 3).

Conclusion

These findings suggest that actigraphy and sleep‐monitoring devices are tolerable for participants with dementia and that the devices can reliably collect valid activity and sleep data in between clinic visits. Sleep efficiency and percentage REM sleep were lower in participants with DLB than in participants with AD. Larger studies should further explore the promise of actigraphy and sleep‐monitoring devices for differentiating DLB and AD.
Assessing the relationship between relational memory and segregation of intrinsic functional brain networks vulnerable to Alzheimer’s Disease during periadolescent development: preliminary findings from the PRANK study
Authors: Phipps Connor J , Sexton Jennifer N , Behm Lillian , DeCesare Thomas A , Heller Abi M , Maerlender Arthur C. , Phatak Vaishali S , Cramer Justin A. , Blair James , Murman Daniel L , Warren David E
Published: December 2022

Background

Alzheimer’s disease (AD) is an insidious disease process that is frequently diagnosed following complaints of memory loss. The AD‐related decline in memory abilities has been attributed to functional and pathological changes in the hippocampus and distributed functional networks supporting hippocampal‐dependent memory. Although AD manifests in late life, lifelong risk factors for AD may be influenced by childhood brain development. The default mode network (DMN) is one functional network associated with the hippocampus and has been well‐characterized in adulthood. However, there is a gap in the literature regarding the connection between DMN network properties and relational memory abilities in childhood. Here we report preliminary findings from our ongoing study (Polygenic Risk of Alzheimer’s disease in Nebraska Kids, PRANK). The PRANK study collects functional MRI, cognitive measures, and AD polygenic risk scores from periadolescent children in Nebraska (age 8‐13 years). Here, we report the current findings measuring the relationship between brain network measures and cognitive outcomes from the PRANK study.

Method

To assess the relationship between intrinsic functional networks of the brain and hippocampal‐dependent memory, we applied brain and cognitive measures from a preliminary sample of periadolescent children (N=90) from the PRANK study. Cognitive assessments measured hippocampal‐dependent memory and other cognitive domains. Brain measures included both structural and resting‐state functional MRI data. Two properties of brain networks were measured, modularity and participation coefficient. These measures were derived from resting‐state MRI data with help of the Human Connectome Project’s Connectome Workbench tool. For comparison, brain and cognitive measures were also collected from a separate dataset of healthy young adults.

Result

Our analysis observed differences between the PRANK and young adult datasets. The observed between‐group differences included graph theoretic measures of network architecture, particularly modularity. The relationship between relational memory performance and the network properties PRANK participants was also assessed.

Conclusion

The ongoing PRANK study seeks to determine the association of brain measures and cognitive performance. Here, our preliminary analysis measured the relationship between brain and cognitive measures in periadolescent children with a focus on brain network properties and relational memory.
Ancestral Analysis of the Presenilin‐1 G206A Variant Reveals it as a Founder Event on an African Haplotype in the Puerto Rican Population
Authors: Hamilton‐Nelson Kara L. , Griswold Anthony J. , Rajabli Farid , Whitehead Patrice L. , Contreras Maricarmen , Tejada Sergio , Sanchez Jose Javier , Mena Pedro Ramon , Adams Larry D. , Starks Takiyah D. , Silva‐Vergara Concepcion , Cuccaro Michael L. , Vance Jeffery M. , Byrd Goldie S. , Haines Jonathan L. , Beecham Gary W. , Feliciano‐Astacio Briseida E. , Pericak‐Vance Margaret A. , Celis Katrina
Published: December 2022

Background

Variants in the presenilin‐1 gene (PSEN1) are known to be pathogenic for Alzheimer disease (AD). The change of glycine at amino acid 206 to alanine (G206A) in PSEN1 has been identified in AD Caribbean Hispanic families from Puerto Rico with variable ages of onset and incomplete segregation (Athan et.al., 2001). Here we set out to confirm the role of G206A in the genetic etiology of AD in Puerto Rico while investigating its ancestral history and founding haplotype.

Method

We performed genotyping and whole genome sequencing (WGS) of 43 AD families (N = 182: 87 AD, 41 MCI, and 44 cognitively unimpaired) and 272 AD, 145 MCI, and 297 cognitively unimpaired unrelated individuals of Puerto Rican background and identified carriers of G206A. Genotyping data were phased using SHAPEIT to identify local ancestry of the PSEN1 haplotype followed by RFMix to estimate the genetic ancestral background (African, European, or Amerindian). Haplotype modeling was performed using MERLIN software.

Result

We identified 19 carriers of G206A among individuals with sequencing data in eight of the 43 families (14 AD, two MCI, one neuropsychiatric disorder, and two cognitively unimpaired individuals under 65 years old). G206A did not completely explain AD in these eight families as six other AD cases in the families did not carry the variant. In the unrelated cohort, we identified 13 carriers (nine AD, one MCI, one Pick’s disease, and two cognitively unimpaired under 65 years old). Local ancestry indicated that the mutation arose on an African ancestral haplotype. However, in screening WGS of individuals of primarily African ancestry from Ibadan, Nigeria (63 AD and 648 controls) and African Americans part of the Alzheimer Disease Sequencing Project (1347 AD, 2290 controls) no other carriers were identified.

Conclusion

Our results support that G206A contributes to AD in the Puerto Rican population, but in AD families does not completely explain the genetic risk. We also show that this variant occurs on a common haplotype across carriers representing a founder event on an African haplotype background in Puerto Rico.
Adapting to reality: Effect of Online Assessments as Compared to In‐Person Assessments
Authors: Pallen Vanessa , Rahmouni Nesrine , Tissot Cécile , Stevenson Jenna , Stevenson Alyssa , Poltronetti Nina Margherita , Bezgin Gleb , Lussier Firoza Z , Therriault Joseph , Kunach Peter , Pascoal Tharick , Servaes Stijn , Savard Melissa , Wang Yi‐Ting , Arias Jaime Fernandez , Chamoun Mira , Mathotaarachchi Sulantha , Vitali Paolo , Gauthier Serge , Rosa‐Neto Pedro ,   McGill University Research Centre for Studies in Aging
Published: December 2022

Background

Neuropsychological evaluations are normally assessed in‐person by a trained psychometrician using a variety of tests representing several domains. The COVID‐19 pandemic has obliged medicine and research to switch to online assessment. However, minimal research has tested the reliability of conducting cognitive evaluations online versus in‐person. This study aims to explore the clinical utility of virtually assisted neuropsychological evaluations in a comparative analysis following the effects of the COVID‐19 pandemic.

Method

62 cognitively unimpaired (CU) individuals from the TRIAD cohort underwent baseline and follow‐up neuropsychological assessments which included the Boston Naming Test (Short Form), BORB‐Object Recognition Task, WASI‐II Matrix Reasoning, WAIS‐III Digit Span, D‐KEFS Category Fluency Tests, Rey Auditory Verbal Learning Test (RAVLT), and Free & Cued Selective Reminding Test (FCSRT). Participants were considered CU when they obtained a CDR score of 0, MMSE ≥ 26, with negative amyloid‐β and tau statuses (global amyloid‐β [18F]AZD4694 <1.55 SUVR and temporal meta‐ROI [18F]MK6240 <1.24 SUVR). Participants were divided into two equally represented groups, both of which completed an in‐person baseline evaluation. 30 participants completed their follow‐up evaluation in‐person and 32 completed their evaluation virtually. A mixed linear regression model was used to assess the difference in the rate of change in scores between cohorts using age, sex, and years of education as covariates.

Result

Follow‐up at‐home neuropsychological test results did not significantly differ from in‐person scores across all domains. Participant demographics are shown in table 1. The Boston Naming Test (Short Form), BORB‐Object Recognition Task, WASI‐II Matrix Reasoning, WAIS‐III Digit Span, D‐KEFS Category Fluency Tests, Rey Auditory Verbal Learning Test (RAVLT), and Free & Cued Selective Reminding Test (FCSRT) yielded p values of 0.47, 0.74, 0.17, 0.28, 0.13, 0.53, and 0.77, respectively.

Conclusion

Scores from our battery were selected to represent the different cognitive domains. Based on our findings, there was no difference when individuals conducted in‐person versus online assessments. These results will allow for the geriatric community to receive the medical assistance they require without having to impose any inconveniences or unnecessary health risks. Additionally, virtual assessments will assist to increase contact for prospective participants which would otherwise not be possible in‐person.
Hypomorphic PERK promotes a maladaptive phenotype in response to pathologic tau
Authors: Lessard Christian B , Tolton Samantha G , Abisambra Jose F. F
Published: December 2022

Background

A major challenge in the field of tauopathies, such as progressive supranuclear palsy (PSP) is identification of effective therapeutic targets. PKR‐like endoplasmic reticulum (ER) kinase haplotype A (PERK‐A) adapts cells undergoing ER stress. PERK haplotype B (PERK‐B) does not resolve ER stress effectively and increases the risk for PSP. The mechanism by which PERK‐A and ‐B confer distinct outcomes remains unknown. The overall hypothesis is that PERK‐B promotes maladaptive response that increases tauopathy outcomes.

Methods

We developed new inducible cell lines, unfolded protein response sensors, and PERK plasmids (‐A, ‐B, and an inactive variant, ‐K). We performed molecular biology approaches in vitro including co‐expression, co‐immunoprecipitation assays, and RNAseq.

Results

We found that unlike PERK‐A, PERK‐B was not an effective modulator of pathological tau species. The transcriptome and translatome of PERK‐A and ‐B are distinct. Surprisingly, the PERK‐A translatome has pro‐survival factors.

Conclusion

PERK‐A confers benefits in tauopathy. The PERK‐A translatome is replete with novel therapeutic targets. PERK‐B data offer novel insights into the pathogenesis and progression of PSP, which may be linked to other tauopathies.
Plasma amyloid‐β profiles and the correlation with neuropsychological performance in patients with cognitive decline
Authors: Lee Jin San , Kim Hyun‐Ho , Park Key‐Chung , Rhee Hak Young , Hwang Kyo Seon
Published: December 2022

Background

This study aimed to investigate the relationship between the level of plasma amyloid‐β (Aβ) and neuropsychological performance in patients with cognitive decline, classified according to amyloid PET positivity using a highly sensitive nano‐biosensing platform.

Method

A total of 44 patients with cognitive decline who underwent plasma Aβ analysis, amyloid PET scanning, and detailed neuropsychological tests were recruited in this study. The participants comprised 20 patients with subjective cognitive decline, 7 with amnestic mild cognitive impairment, and 17 with probable AD dementia. Patients were classified into a normal control (NC, N = 25) or Alzheimer’s disease (AD, N = 19) group based on amyloid PET positivity. Multiple linear regression was performed to determine whether plasma Aβ (Aβ40, Aβ42, and Aβ42/40) levels were associated with neuropsychological test results.

Result

The plasma levels of Aβ42/40 were significantly different between the NC and AD groups and were the best predictor of amyloid positivity by receiver operating characteristic curve analysis. There were significant differences in the neuropsychological performance of cognitive domains (language, visuospatial, verbal/visual memory, and frontal/executive functions) between the NC and AD groups. However, in multivariate regression analysis, upon inclusion of age, education, vascular risk factors, and apolipoprotein E ε4 status, higher levels of plasma Aβ42/40 showed significant negative correlations with verbal and visual memory performance, including immediate recall, delayed recall, and recognition tests.

Conclusion

We suggest that our study might have clinical significance because plasma Aβ analysis using a highly sensitive nano‐biosensing platform could not only be a useful non‐invasive method for diagnosing AD, but also showed a significant association with memory performance in patients with cognitive decline. Further investigations with a larger sample size are necessary to clarify the possible relevance of plasma Aβ as a blood‐based biomarker for precise AD diagnosis.
Smartphone‐based long‐term delayed memory performance is associated with the Preclinical Alzheimer's Cognitive Composite and CSF levels of β‐amyloid
Authors: Öhman Fredrik , Berron David , Skoog Johan , Bodin Timothy Hadarsson , Kern Silke , Zettergren Anna , Papp Kathryn V. , Zetterberg Henrik , Blennow Kaj , Skoog Ingmar , Schöll Michael
Published: December 2022

Background

Remote and unsupervised cognitive testing using smartphones may improve sensitivity to detect preclinical Alzheimer’s disease (AD). In particular, cognitive testing at‐home enables the evaluation of the potentially more sensitive long‐term delayed memory retrieval, which is commonly not feasible in a clinical setting.

Method

Here, we investigated the association between remote and unsupervised smartphone‐based cognitive assessments and in‐clinic cognitive measurement in older participants (CDR = 0, MMSE = 29.2, age = 77). The sample (non‐demented at age 70) was derived from the Swedish population‐based Gothenburg H70 Birth Cohort Studies. In a subsample of participants, the retrospective correlation with cerebrospinal fluid (CSF) biomarkers analyzed at age 70 was further explored. To this point, 177 H70‐participants have consented and were enrolled into the smartphone sub‐study. They completed an “Object‐in‐Room Recall Test“ (ORR) remotely and unsupervised using own mobile devices, and the recall session was initiated 24 hours after the initial learning phase. Available previously assessed CSF measures included the Aβ42/Aβ40‐ratio, t‐tau, p‐tau, neurofilament light (NFL), and neurogranin, available in‐clinic cognitive tests included the Rey Auditory Verbal Learning Test (RAVLT), Semantic Fluency, Digit‐Symbol‐Coding, and Mini Mental State Examination. The above‐mentioned cognitive tests were used to derive the Preclinical Alzheimer's Cognitive Composite (PACC5), a composite designed to be sensitive to cognitive change in preclinical AD. All associations were examined using Pearson correlation coefficient.

Result

Preliminary analyses in a subset of participants yielded relatively strong positive correlations between PACC5 (R = .50, p<.001) and the ORR Long‐term Delayed Retrieval. The strongest correlation for an individual test was observed between the RAVLT Delayed Retrieval and the ORR Long‐term Delayed Retrieval (R = .52, p<.001). Regarding the CSF biomarkers, Aβ42/Aβ40‐ratio at age 70 was positively correlated with the ORR Long‐term Delayed Retrieval at age 77 (R = .43, p<.01), while measures of t‐tau, p‐tau, NFL, and neurogranin at age 70 were not.

Conclusion

Our findings demonstrate the potential of smartphone‐based cognitive assessment to detect features of preclinical AD in a population‐based sample of older adults. Future analyses will address the relationship between these novel cognitive measures in relation to longitudinal CSF‐ and neuroimaging‐based biomarkers and clinical progression.
Differential item functioning of the CSI’D in the MexCog
Authors: Cantu Phillip A , Garcia Joshua M
Published: December 2022

Differential item functioning of the CSI’D in the MexCog

Background

Previous research shows that Spouse and Child informants in the MexCog report higher levels of cognitive impairment than other family and non‐family informants, even when controlling for direct cognitive assessments. The question remains, are the higher levels of cognitive impairment reported by spouses and children because they are informants for the most impaired older adults or because they respond to the questions differently? Additionally, direct cognitive assessments of low education populations may downwardly bias results. Individuals who are illiterate or who have had no formal schooling may score worse on cognitive assessments due inability to answer questions that require reading and writing or unfamiliarity with testing in general. The extent to which informant assessments of cognition can be used to better capture cognitive impairment for low educated population has not been studied.

Methods

Using item response theory (IRT) we examine the extent to which there is differential item functioning (DIF) between different types of informants and other associated with lower direct assessment for the Community Screening Interview for Dementia (CSI’D).

Results

The anticipated results of this study will allow us to compare the observed CSI’D Score to an IRT weighted CSI’D score, controlling for DIF. The difference in observed and IRT weighted CSI’D score will show to what extent the differences in CSI’D score are due to differences in measurement.

Conclusion

The item level bias, or lack of, will shed light on the importance of informants in measurement of cognitive impairment. Knowing how different informants answer informant questionnaires could have important implications for population‐based studies of cognitive decline.
Neuroinflammation co‐localizes highly with tau in amnestic mild cognitive impairment
Authors: Appleton Johanna , Funk Quentin , Bradbury Kathleen , Yu Meixiang , Faridar Alireza , Beers David , Appel Stanley H , Fujita Masahiro , Masdeu Joseph C. , Pascual Belen
Published: December 2022

Background

Neuroinflammation, along with beta amyloid and tau brain deposition, is a potential diagnostic biomarker and therapeutic target in patients with Alzheimer’s disease (AD). The role of inflammation at various stages of the AD process needs to be clarified. TSPO PET is useful to image brain inflammation, but some tracers have low affinity for TSPO and “second generation” tracers, with higher affinity, cannot image subjects with a low‐binder TSPO rs6971 genotype. We overcame this problem by using 11C‐ER176, a high‐affinity tracer allowing for imaging of all participants and with a more favorable metabolite profile than other high affinity tracers (Fujita, 2017). Then, we correlated the localization of neuroinflammation tau and amyloid in a subset of the participants.

Method

We imaged 15 patients with amnestic MCI (mean age 63±5, 7 women) and 15 healthy controls (HC) (8/15 women, mean age 65 ±7) using 11C‐ER176 PET. TSPO affinity was similar (MCI/HC = 2/3 low, 8/7 mixed, 5/5 high). A full factorial analysis was performed on V
T values between groups at the regional level (Hammer’s atlas). Ten MCI patients had also amyloid PET (18F‐florbetaben or 18F‐florbetapir) and tau PET (18F‐flortaucipir). Standard uptake value ratios (SUVRs) were calculated for both tracers using the cerebellum as reference. Regional correlations among the three tracers were determined for each patient and an average calculated. All images were corrected for partial volume effect.

Result

Neuroinflammation in MCI was bilaterally increased in precuneus and lateral temporo‐ parietal cortex, and right amygdala. There was a correlation between the localization of amyloid and tau in the brain (r=0.61). However, the correlation between neuroinflammation and tau was even higher (r=0.73); neuroinflammation also co‐localized with amyloid, but not as strongly (r=0.59).

Conclusion

11C‐ER176 PET allowed for the identification in MCI of neuroinflammation in regions known to be involved in the AD process. Importantly, all subjects with any TSPO genotype could be studied. As expected, the localization of amyloid and tau in the brain was correlated, but the co‐localization of neuroinflammation with tau was even higher than between amyloid and tau. This finding highlights the importance of neuroinflammation as a biomarker of neurodegeneration and as a therapeutic target.
Assessing trust and research attitudes in Blacks/African Americans following a personalized vs less personalized community approach
Authors: Bouges Shenikqua , Noell Debra , Osman Fauzia , Benton Susan Flowers , Clipps Antwon D , Fischer Barbara L. , Gooding Diane C. , Anthony Ruben L , Carter Fabu P , Salazar Hector , Simó Carola A. Ferrer , Ennis Gilda E. , Van Hulle Carol A. , Zuelsdorff Megan , Wyman Mary F. , Johnson Adrienne L. , Lambrou Nickolas H. , James Taryn T. , Carlsson Cynthia M. , Asthana Sanjay
Published: December 2022

Background

Several studies have shown the importance of establishing trust in supporting an individual’s willingness to participate in research; yet evidence is limited regarding systematic studies testing the effectiveness of various methods used to build trust. Our pilot study examined two methods of building trust in communities of color by measuring willingness to participate in research pre‐ and post‐intervention. We hypothesized that a more personalized intervention would be more effective than a non‐personalized one in changing attitudes about research participation.

Methods

97 non‐randomized African American participants, without self‐reported cognitive impairment, completed the research attitudes questionnaire (RAQ) before and after participating in two different community engagement (CE) activities: 1) personalized medication review (MR), n = 48; and/or 2) a less personalized public community talk (Talk), n = 49. Numeric comparisons were conducted using student t‐tests. We used chi‐square and Fisher’s exact test for categorical comparisons. Pre‐ and post‐Talk and MR outcomes were tested for significant changes using the paired Wilcoxon non‐parametric sign rank test.

Results

In this predominantly female sample (80% female), mean age was 64 (standard deviation = 9.9). Study participant characteristics provided in Table 1. There were no significant differences in RAQ or trust questions in the pre‐ and post‐Talk session. However, during the MR session, significant changes were seen on the question “I have a positive view about medical research in general” (P = 0.007). During the pre‐MR, 16.7% strongly agreed with this statement, while 39.6% strongly agreed at the post‐MR. Similarly, agreement with the statements “Medical researchers treat people from my racial group as guinea pigs” (p = 0.004) and “Medical researchers work hard to keep participants’ information private and secure” (P = 0.01) were also significantly different following the intervention (see Figure 5).

Conclusions

These findings support our hypothesis that a more personalized community engagement approach would have a greater influence on participant’s research attitudes. Compared to individuals with ≤ 1 co‐morbidities at baseline, those with ≥2 co‐morbidities had positive responses prior to an intervention and felt less responsibility to volunteer post med review. Additional studies are needed to further investigate these findings and the role of trust in association with research attitudes.
Use of Cognitive Training in an Outpatient Memory Clinic
Authors: Anderson Allan A , Ashish Dev
Published: December 2022

Background

Patients with MCI or mild AD often search out non‐pharmacologic treatments to improve their cognitive deficits or aid in managing them. At BAI Tucson we developed a multi‐component and multi‐domain cognitive training program with patients and care partners.

Method

Individual sessions of cognitive training are provided to select patients at our outpatient memory center.

Result

Patients often benefit with improved productivity at work and in their personal lives. They also improve emotionally with increased self confidence in their day‐to‐day activities. Outcomes of post treatment interviews validate these benefits.

Conclusion

Cognitive training can be a powerful tool for use in outpatient memory clinics offering an alternative to pharmacologic treatments. Data demonstrate improvements in quality of life measures including improved mastery of daily activities, improved self esteem, and reduced complaints of cognitive dysfunction.
Plasma p‐tau181 concentration accurately predicts clinically diagnosed Alzheimer’s Disease cases
Authors: Kumar Pankaj , Vanbrabant Jeroen , Encarnacion Mary , Mousavi Ali , Mammel Anna , Aziz Tariq , Hsiung Ging‐Yuek Robin , Vanmechelen Eugeen , Stoops Erik , Frykman Hans
Published: December 2022

Background

The feasibility of detecting tau phosphorylated at threonine‐181(p‐tau181) in CSF makes it a valuable biomarker for diagnosis in the field of Alzheimer’s Disease (AD). Recently, the novel technologies accurately measuring biomarkers directly in blood offer a unique advantage for use in clinical testing and trials. This study describes the performance testing of a novel plasma p‐tau181 Simoa assay to predict clinical AD.

Method

The presented data were obtained after analysis of EDTA plasma from cases with clinical AD who had been referred to the UBC Hospital Clinic with complaint of cognitive impairment and were assessed for dementia and AD between 2008 – 2018.

We also analysed serum of 50 random healthy donors and 50 aged ‐ matched controls with normal cognition. The samples were assayed using an ADx Neurosciences developed p‐tau181 specific Simoa assay. Analytical performance (precision, detection limit, parallelism) and analyte stability was evaluated using healthy‐donor samples. Finally, the p‐tau181 specificity was assessed using synthetic peptides.

Result

254 AD patients (female = 125) and 100 controls (female = 39) were included. The average of plasma p‐tau181 was 72.9 ±36.8 ng/L in AD cases and the average of serum p‐tau181 was 8.1± 10.5 ng/L in controls.

The concentration of plasma p‐tau181 in patients with AD was significantly increased with at‐least 9‐fold versus controls (p=<0.001). ROC analysis demonstrated an AUC of 0.92 and a suitable clinical cut‐off of 34.3 ng/L. Analytical performance testing: 1 of the 254 AD samples tested were below the LLOQ of 1.38 ng/L. The intra‐ and inter‐ assay variability was 8.2% CV and 11.8 % CV, respectively. Sample dilution (df 2‐4‐5‐6) resulted in mean parallelism of 93.5 %. P‐tau181 levels were stable up to 5 Freeze/Thaw cycle (mean 98.9%) and up to 24h at 4°C or RT. The assay was found to be highly specific towards p‐tau181 and nonreactive to p‐tau175.

Conclusion

The plasma p‐tau181 concentration in AD cases were significantly higher than controls with limited overlap and in line with published data. The specific measurement of plasma p‐tau181 shows good promise in offering a non‐biased measurement and help in the clinical assessment of AD patients and clinical trials.