bluuebunny/crossref_metadata_2025 huggingface dataset:
User experience and biomarker associations of remotely administered and unsupervised smartphone‐based cognitive testing in a community sample of older adults
Authors: Öhman Fredrik , Bosch Iris , Berron David , Srikrishna Meera , Heeman Fiona , Skoog Johan , Zettergren Anna , Papp Kathryn V. , Blennow Kaj , Zetterberg Henrik , Kern Silke , Skoog Ingmar , Schöll Michael
Published: December 2023

Background

Remotely administered, unsupervised smartphone‐based cognitive tests have the potential for scalable and cost‐effective screening of Alzheimer’s disease (AD) in clinical trials and primary care. Previous work has provided initial evidence for the feasibility and validity of these tools in clinical and community settings. However, more studies investigating the utility of these cognitive tests are warranted, particularly regarding user experience and the association with AD biomarkers.

Method

To date, 198 participants (CDR 0 = 85%, CDR 0.5 = 15%, Mini‐Mental State Examination = 29, average age = 77) have enrolled in this smartphone sub‐study, a part of the Swedish population‐based Gothenburg H70 Birth Cohort Studies. After participating for at least 12 months, the user experience of smartphone‐based cognitive tests (two memory tests, MDT‐OS and ORR‐LDR) was assessed. Furthermore, we investigated their associations with volumetric brain changes based on magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers (Aβ42/Aβ40 ratio, T‐tau, P‐tau, NFL, and neurogranin). The latter will be analyzed in a subsample (n = 45 for CSF and n = 110 for MRI) of all participants. Voxel‐based analyses are being performed in SPM12.

Result

Most study participants found the app easy and enjoyable to use, the instructions easy to understand, and they generally favored performing tests in their home environment. Low CSF Aβ42/Aβ40 ratio at age 70 was associated with worse performance on the ORR‐LDR at age 77 (R = .43, p<.002), while measures of t‐tau, p‐tau, NFL, and neurogranin at age 70 were not. Voxel‐wise associations between smartphone‐based cognitive tests and MRI measures will be reported at the conference.

Conclusion

Our results suggest that using smartphone‐based cognitive tests in a remote unsupervised setting has the potential to identify aspects of early AD in a community‐based setting. The positive user experience is promising for acceptance of these novel tools for cognition assessment. Next steps include analyses of the relation with neuroimaging‐based biomarkers.
Early‐life bilingualism could protect from age‐related gray matter volume loss in the left caudate – preliminary results
Authors: Schumann‐Werner Beate , Molloy Eóin N. , Fischer Larissa , Schwarck Svenja , Hochkeppler Anne , Vockert Niklas , Büchel Anna‐Therese , Sick Florian , Werner Cornelius Johannes , Kreißl Michael C. , Düzel Emrah , Maass Anne
Published: December 2023

Background

Early‐life bilingualism (i.e., second language acquisition before the age of 30) has been shown to confer benefits in separate cognitive domains later in life, possibly contributing to the concept of cognitive reserve. However, the effects of early‐life bilingualism on cognitive performance and gray matter volume (GMV) in the elderly have been studied scarcely. In an ongoing cohort, we examined the influence of early‐life bilingualism on cognitive performance (e.g., phonemic fluency as tested by the Regensburg word fluency test (RWT), among others) as well as age‐related brain gray matter volume in older adults.

Method

We analysed 3‐Tesla T1‐weighted Multi‐Echo MPRAGE and cognitive data from 25 healthy adults (72.8±7.69 years, 10 female) in our new cohort established within the CRC1436 (https://sfb1436.de/). Assessment of bilingualism was conducted using the Lifetime of Experiences Questionnaire (LEQ). MRI data were preprocessed and analysed using FSL‐VBM. We performed a whole‐brain analysis looking for an interaction between age and bilingualism on GMV values, postulating that early bilingualism might contribute to a preservation of gray matter along the age trajectory. We extracted GMV values from significant regions of interest (ROIs) and looked for correlations with cognitive performance. Due to the small cohort and the preliminary nature of these analyses, we chose an exploratory threshold of p<0.001 (uncorrected) for the whole brain analysis. ROIs were defined by a threshold of p<0.1 cluster‐corrected (z>3.1).

Result

Participants with early‐life bilingualism (n = 7) had significantly more years of education (p<0.05) and performed better in the RWT (p<0.05) than monolinguals (n = 18). The age‐bilingualism interaction term across the whole brain (adjusted for education) identified the head of left caudate nucleus as being protected from age‐related GMV loss by early‐life bilingualism (Fig. 1). The age‐GMV‐relationship for both groups is shown in Fig. 2. We observed no significant relationship between GMV in the left caudate and performance in any cognitive tests.

Conclusion

These preliminary results hint at a role of early‐life bilingualism in modulating GMV in older adults. How these relate to better cognitive performance remains to be elucidated. Moreover, considering brain areas not typically studied in cognitive aging, such as the basal ganglia, seems worthwhile.
Using machine learning of neuroimaging patterns combined with mitochondrial genomics to predict maternal inheritance of Alzheimer’s disease
Authors: Veatch Olivia J , Dutta Sreejata , Mansel Clayton , Townley Ryan A , Sardiu Mihaela E , Honea Robyn A
Published: December 2023

Background

Maternal family history (FHm) contributes increased risk for developing Alzheimer’s disease (AD) compared to paternal. Family history is often unknown, making it difficult to identify these higher‐risk patients. Atrophy patterns indicative of AD relate to parent‐of‐origin effects. Risk factors may also include mitochondrial variation (mtDNA). Machine learning (ML) approaches could identify predictive traits for FHm, helping detect higher‐risk patients with unknown family history. We aimed to determine if structural MRI variables and mitochondrial haplogroups could classify FHm.

Method

Using data from the National Alzheimer’s Coordinating Center and NIA Genetics of Disease Storage Site, we determined if a feature set, comprised of structural MRI variables and mitochondrial haplogroups, could accurately predict FHm. Haplogroups were called with HaploGrep v2.4.0 based on the PT17‐FU1 reference. Two‐thirds of the dataset was used for training and one‐third for testing. For hyper‐parameter tuning and optimization of model performance, we used 4‐fold cross‐validation. To identify traits that aid in predicting FHm, feature importance was calculated for the best performing model (selected based on accuracy and AUC).

Result

ML models were initially trained on imaging variables for 961 individuals (60% female) with confirmed positive (69%) or negative (31%) FHm. Average age at MRI was 68±11 years old. XGboost emerged as the best method (Accuracy = 0.62, AUC = 0.56). Feature importance calculations indicated precuneus was the most important. Including haplogroups significantly reduced the sample size (n = 602) and model performance. Most of the dataset (87%) were assigned to mitochondrial haplogroups within the R branch. Notably, although model performance was reduced, precuneus remained one of the most important variables.

Conclusion

This analysis was among the first to explore if structural or genomic traits predicted FH. Although performance for the initial models showed moderate accuracy, we are currently testing additional ML approaches to enhance predictivity. We identified the precuneus as a key‐AD‐vulnerable region associated with FHm. Our study contributes to a growing literature showing structural, neurodegenerative, cerebral metabolic and increased amyloid‐β burden in the precuneus of individuals with FHm. Analyses aimed at more comprehensive evaluation of mitochondrial genomic variation that expands upon haplogroup classification are ongoing to clarify the role mtDNA plays in maternally inherited AD.
Effects of hearing intervention on cognitive decline: Results of the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) randomized trial
Authors: Lin Frank R , Pike James R. , Albert Marilyn S. , Arnold Michelle L , Burgard Sheila , Chisolm Theresa , Couper David , Deal Jennifer A , Goman Adele M , Glynn Nancy W. , Gmelin Theresa , Gravens‐Mueller Lisa , Hayden Kathleen M. , Huang Alison R , Knopman David S. , Mitchell Christine , Mosley Thomas H. , Pankow James , Reed Nicholas S , Sanchez Victoria A , Schrack Jennifer A , Windham B Gwen , Coresh Josef ,   ACHIEVE Collaborative Research Group
Published: December 2023

Background

Hearing loss is associated with greater cognitive decline and incident dementia. Whether hearing intervention could reduce cognitive decline in older adults with hearing loss is unknown.

Method

The ACHIEVE study is a randomized trial (NCT03243422) of 70‐84 year‐old adults with untreated hearing loss and free from substantial cognitive impairment that took place at four U.S. sites. Participants were recruited from two study populations: 1) a group of adults participating in a longstanding observational study of cardiovascular health (Atherosclerosis Risk in Communities [ARIC] study), and 2) a group of healthy de novo community volunteers. Participants were randomised (1:1) to hearing intervention (HI; audiological counseling and provision of hearing aids) or a successful aging health education control intervention (SA; sessions with a health educator on chronic disease prevention). The primary intention‐to‐treat endpoint was 3‐year change in a global cognition standardized factor score from a comprehensive neurocognitive battery.

Result

977 participants (238 ARIC, 739 de novo) underwent randomisation; 490 were assigned to HI and 487 to SA control. Participants from ARIC were older, had more risk factors for cognitive decline, and had lower baseline cognitive scores than the de novo group. In the primary analysis combining the ARIC and de novo groups, 3‐year cognitive change (in S.D. units) was not significantly different between HI and SA control (HI: ‐0·200 [95% CI: ‐0·256,‐0·144]; SA: ‐0·202 [‐0·258,‐0·145]; Difference 0·002 [‐0·077,0·081],p = 0·96). However, prespecified analyses demonstrated significant differences in the effect of HI on cognitive change between the ARIC and de novo group (p interaction = 0·010). In the ARIC group, HI was associated with a 48% reduction in 3‐year cognitive change compared to SA control (HI: ‐0·211 [‐0·349,‐0·073]; SA: ‐0·402 [‐0·536, ‐0·267]; Difference 0·191 [0·022,0·360,p = 0·027]). In the de novo group, cognitive change was not significantly different between HI and SA control (HI: ‐0·213 [‐0·277,‐0·148]; SA: ‐0·151 [‐0·215,‐0·087]; Difference ‐0·061 [‐0·151,0·028,p = 0·18]). The rate of cognitive change among control participants was observed to be 2.7‐fold faster in the ARIC versus de novo group.

Conclusion

Hearing intervention may have a significant effect on reducing cognitive change over 3 years in populations of older adults at increased risk for cognitive decline.
Cognitively Impaired Subjects with Normal Total Cholesterol Using Lipophilic Statins Undergo Accelerated Decline in Regions Associated with Dementia and Those Regions are Predictive of Further Decline Over the Subsequent Two‐Year Period in a Multi‐Center Longitudinal Study
Authors: Padmanabham Prasanna S. , Liu Stephen S. , Silverman Daniel H.
Published: December 2023

Background

We recently reported that lipophilic statins, known to penetrate the blood‐brain barrier, were associated with accelerated decline in cortical regions known to decline in early Alzheimer’s Disease, in subjects with early Mild Cognitive Impairment (eMCI) having normal cholesterol levels. We now report the predictive value of the pattern of regional metabolism in forecasting severity of decline over the subsequent two years.

Method

Subjects were drawn from a consecutive series enrolled in the Alzheimer’s Disease Neuroimaging Initiative, identifying 70 with eMCI having serum cholesterol levels below the 206 mg/dl median of non‐statin users and with clear histories of time‐frames of prescriptions and types of statins. FDG‐PET scans acquired at baseline and two years later were compared for each group, and rates of regional metabolic decline were determined.

Result

In direct statistical comparisons on a voxel‐by‐voxel basis, subjects on lipophilic statins (LS) underwent significantly greater decline in posterior cingulate (PCC) and right parietotemporal cortex (rPTC) compared to those not on statins (p<0·0005). Moreover, baseline rPTC metabolism was positively correlated with magnitude of left inferior parietal metabolism two years later in LS subjects (p = 0.008), but not in nonS subjects (p = 0.95). Conversely, baseline parietal metabolism was not correlated with subsequent rPTC metabolism in either group of subjects. In addition, based on regional network analysis, LS subjects had greater functional connectivity in the medial temporal regions.

Conclusion

Subjects with eMCI and normal range cholesterol levels taking lipophilic statins suffered faster metabolic decline of brain regions affected by early Alzheimer’s disease, and baseline activity in those regions predicted further decline over the subsequent two years in associative cortex. Moreover, the pattern of functional connectivity with medial temporal regions was altered in subjects on these statins.
Interpretable deep learning framework towards understanding molecular changes associated with neuropathology in human brains with Alzheimer’s disease
Authors: Joshi Amogh Manoj , Shah Jay , Readhead Benjamin , Su Yi , Wu Teresa , Wang Qi
Published: December 2023

Background

Postmortem brain tissues have been used to characterize some of the molecular networks and drivers associated with Alzheimer’s disease (AD). In this study, we extend our previous work of a deep learning approach to characterize the molecular changes associated with the severity of AD‐related neuropathology and cognitive impairment, by applying the framework to different brain regions with larger sample sizes.

Method

We trained multi‐layer perceptron (MLP) models for classification of neuropathologically confirmed AD vs. healthy controls (HC) using the transcriptomic data of three brain regions (dorsolateral prefrontal cortex (DLPFC, Total N = 1092), posterior cingulate cortex (PCC, Total N = 647), and head of caudate nucleus (HCN, Total N = 717)) respectively from the ROSMAP study. We performed z‐score normalization for each gene expression and randomly split data in ratio 80:20 with matching class (AD and HC) distributions for training and testing. We embedded the expression profiles of all the subjects to the same Uniform Manifold Approximation and Projection (UMAP) space using the final layer of the trained models and obtained progressive trajectories that mirrored AD pathological severity and cognitive impairment of the whole cohort. Interpretable technique SHapley Additive exPlanations (SHAP) was explored to explain model predictions and obtain significant genes contributing to AD. Network analysis was then carried out to identify key gene modules presented in the models underlying AD progression of different brain regions.

Result

The MLP models differed for each dataset with the number of layers ranging between 3‐5 and achieved the best AUC of 0.891, 0.940 and 0.776 on DLPFC, PCC and HCN datasets respectively. The AD severity indexes (SI) calculated from the trajectory were highly correlated with neuropathology biomarkers (R ∼ 0.6, p < 1e‐11) and global cognitive function (R ∼ 0.7, p < 2.2e‐16). Significant genes identified by the SHAP explainer revealed common and specific transcriptomic signatures from different brain regions implicated in AD.

Conclusion

This study illustrates the potentials of deep learning methods to multi‐omic data to characterize the molecular networks associated with increasingly severe clinical and neuropathological stages of neurodegenerative diseases like AD. This offers the opportunity to discover drug targets and/or biomarkers.
Emerging Strategies for Developing Highly Engaging Dementia Care Intervention for Paid Care Workers in Long‐Term Care (LTC) Settings
Authors: Levkoff Sue E , Chen Hongtu , Cortes Dharma
Published: December 2023

Background

There is widespread agreement about the need for strengthening the dementia‐capable workforce to increase the accessibility of online dementia care training programs for paid care workers (PCW) in LTC. Through three NIH‐funded research projects, we are forming an approach to the development of digital dementia training interventions based on two main strategies: a) improving ‘engage‐ability’ by using an engagement design centering on the concepts of motivation (key needs of the user), satisfaction (positive experience with the intervention), and interactivity (connection from one session to another); and b) integrating domain‐specific employee training with a generic employee wellness program.

Method

Study 1 evaluates a self‐directed learning (SDL) digital dementia care training intervention to increase ‘engage‐ability’ by addressing PCWs’ needs for improved knowledge and competence for caregiving while maintaining a sense of control in the learning process (motivation); by enhancing the ease of use through scenario‐based audiovisual modules (satisfaction); and, by using post‐session quizzes and pre‐session reminder messages (interactivity). Study 2 developed a worksite digital health risk assessment combined with a wellness improvement program that enabled a workplace counselor to deliver health education materials to increase healthy lifestyle behaviors in preretirement adult workers aged 55 and above. Study 3 combines the SDL dementia care training with the wellness program for PCWs in LTC settings in order to achieve high ‘engage‐ability’ and acceptability of the intervention.

Result

A pre‐post evaluation of the SDL program (Study 1) revealed a significant reduction in stress and improved self‐efficacy in providing dementia care among PCWs (Study 1). Formative research demonstrated moderate usability and acceptability from the pre‐retirement workers who participated in Study 2. In Study 3, focus groups with PCWs and managers from LTC organizations showed high endorsement of integrated dementia care training and wellness programs with organizational support for the delivery of the training intervention for PCWs in LTC settings.

Conclusion

A successful digital training program for PCWs providing dementia care in LTC systems requires an integration of dementia‐specific training and the tools for wellness critical for supporting PCWs’ overall well‐being while securing support from the LTC organizations for PCW participation in the program.
Influence of amyloid and diagnostic syndrome on non‐traditional memory scores in early‐onset Alzheimer’s disease
Authors: Bushnell Justin , Hammers Dustin B. , Apostolova Liana G. , Kramer Joel H. , Carrillo Maria C. , Dickerson Brad C. , Rabinovici Gil D. , Clark David G.
Published: December 2023

Background

The Rey Auditory Verbal Learning Test (RAVLT) is a neuropsychological test used for assessing episodic memory impairment. The sequence of the RAVLT consists of five learning trials, an intrusion list recall, a subsequent recall (short delay), and a delayed recall (approximately thirty minutes after the short delay recall). The RAVLT has been studied extensively in various presentations of dementia, but there is limited research for early‐onset Alzheimer’s disease (EOAD). We analyze the influence of amyloid and diagnostic syndrome on traditional and novel RAVLT scores in EOAD.

Method

We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS). Subjects were group by amyloid status (control/EOnonAD vs EOAD) and syndrome: posterior cortical atrophy (PCA), primary progressive aphasia (PPA), amnestic, and non‐amnestic presentations. The traditional method of scoring the RAVLT is to count the total number of correct words recalled for each task (i.e., raw score). Two other count‐based scores were calculated by examining serial position effects (SPEs). SPEs describe the tendencies to remember words in the beginning (primacy) or end (recency) of the list. A relational SPE score, known as J‐curve, is examined here and is defined as primacy minus recency. Three timing‐based scores were analyzed: duration, stopping time, and speed. The seven scores were entered separately into linear mixed effects models as dependent variables. Amyloid status, syndrome, and nuisance variables (age, sex, education) were entered as independent variables.

Result

Compared with amyloid‐negative subjects, amyloid‐positive subjects showed negative effects on raw score, primacy and recency. The presence of amyloid increased stopping time by 5%. Duration and speed were not found to be associated with amyloid. Significant differences among clinical syndromes were observed with recency, duration, and stopping time.

Conclusion

RAVLT measures are sensitive to the effects of amyloid and syndrome in early‐onset dementia. Stopping time is a novel score that may complement existing measures for describing amyloid‐positive individuals. Further work is needed to quantify the predictive value of these scores.
Cognitive health disparities and COVID‐19 stress: Evidence from metro‐Detroit
Authors: Ajrouch Kristine J , Brauer Simon , Zahodne Laura B. , Antonucci Toni C
Published: December 2023

Background

Racial/ethnic minority groups and those with lower socioeconomic status suffer greater prevalence of cognitive health problems. For example, older Black Americans are about twice as likely to develop ADRD as older Whites (Lennon et al., 2022). Rates of ADRD are unknown among Middle Eastern/Arab Americans (MENA). Throughout the COVID‐19 pandemic, racial/ethnic disparities existed such that COVID‐19 prevalence and mortality were greater among Black and MENA populations compared to Whites (Dallo et al., 2022). This paper characterizes COVID‐19 stress prevalence and cognitive health in metro‐Detroit among three racial‐ethnic groups.

Method

In the recently completed U.S.‐based Detroit Area Wellness Network – COVID‐19 Supplement (DAWN‐CS) project (N = 606), participants were recruited from an existing longitudinal cohort study (i.e., Social Relations Study; Antonucci & Akiyama, 1994), supplemented by address‐based and respondent‐driven sampling in order to obtain a racially/ethnically balanced sample of MENA, Black, and White older adults. Eligible persons (aged 65+) within screened households were selected with probability to allow appropriate inference to the target population. Inclusion criteria for DAWN‐CS were: age 65+, fluency in English or Arabic, and identifying as MENA, Black, or White. Psychosocial questionnaires and cognitive measures were administered via telephone. Global cognition was a composite score of episodic memory, language, attention, and working memory tests.

Result

MENA older adults reported more COVID‐19 stress and demonstrated lower cognitive health than White older adults, aligning more with profiles observed among Black older adults. The influence of COVID‐19 stress did not vary by race‐ethnicity or predict cognitive health in the whole sample. COVID‐19 stress predicted better cognitive health only for Whites.

Conclusion

Including underrepresented populations in the study of stress and cognitive health advances science and addresses societal health in its entirety. Disaggregating MENA from Whites demonstrates an unrecognized disparity (MENA versus White older adults), and improves estimates of other disparities (Black versus White older adults). The benefit of stress on cognitive health for Whites reflect that stress may have health benefits when experienced in small doses.
12‐month cognitive outcome after acute geriatric TBI not associated with U.S. Military Veteran status
Authors: Kornblith Erica S , Huie Russell , Manly Geoffrey , Mukherjee Pratik , Yaffe Kristine , Tarapore Phiroz , Yuh Esther C. , Gardner Raquel C.
Published: December 2023

Background

Traumatic brain injury (TBI) increases risk for cognitive decline and Alzheimer’s disease/related dementias (ADRD), and Veterans may be at increased risk of both TBI and cognitive decline due to combat/training related exposures and other risk factors. However, it is unknown whether older Veterans are more likely to experience a poor cognitive outcome after acute TBI compared to civilians.

Method

We examined 112 male Veterans and 320 male civilians (55+) who experienced an acute TBI and enrolled in Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK‐TBI). Data were collected at baseline (i.e., emergency room visit) on demographic and injury characteristics. Cognitive and TBI recovery data (i.e., Rivermead Postconcussive Questionnaire, Brief Symptom Inventory, Satisfaction with Life Scale, and Glascow Outcome Scale‐Extended) were collected at 2 weeks, 6 months, and 12 months. We calculated descriptive statistics and compared across Veterans and civilians. 12‐month cognitive outcome was defined as performance <9th percentile on 2+ cognitive tests, and/or decline from 2‐week or 6‐month score >90% reliable change index on two+ tests. We used propensity weighting to address missing cognitive outcome data and conducted a logistic regression analysis to examine association of Veteran status with classification of cognitive outcome.

Result

Veterans were older and less likely to be Hispanic compared to civilians but did not differ on race, education, history of head injury, or injury severity. At 12 months post‐TBI, Veterans endorsed worse mood and satisfaction with life (p’s = 0.05), but these results were attenuated by adjustment for prior TBI and injury severity. In adjusted models Veterans did not differ from civilians on a measure of overall TBI outcome (p = 0.45) or postconcussive symptoms (p = 0.32). Moreover, there was no association between Veteran status and cognitive outcome (Wald chi square = 2.66, p = 0.45).

Conclusion

Risk of poor cognitive outcome following TBI does not differ between older male Veterans and civilians, and mood and life satisfaction outcomes were worse for Veterans but impacted by injury severity and prior head injury. These findings have implications for understanding risk for cognitive decline and ADRD among older men who experience an acute TBI as well as tailoring care, including provision of psychosocial support, for these patients.
Tau PET accumulation in Brodmann areas 35 and 36 is associated with individual differences in cognition in non‐demented older adults
Authors: Rani Nisha , Alm Kylie H. , Speck Caroline L , Soldan Anja , Pettigrew Corinne , Zhu Yuxin , Albert Marilyn S. , Bakker Arnold
Published: December 2023

Background

Mounting evidence indicates that tau accumulation in the entorhinal cortex (EC) occurs early in the course of Alzheimer’s disease (AD). Recent advances in automated segmentation methods allow for the investigation of smaller regions of the medial temporal lobes (MTL), including subregions of the EC. This study examined tau deposition in relation to individual differences in cognition among older adults, assessing whether MTL subregions explained a greater proportion of variance in cognition, when compared to standard labeling methods.

Method

Analyses included 91 BIOCARD study participants who were cognitively unimpaired (CU; n = 82) or had mild cognitive impairment (MCI; n = 9). Stepwise linear regressions were used to examine the contributions of regional tau burden to individual differences in the CDR sum of boxes (CDR‐SB), MMSE, and composite scores of global cognition and memory. Other model variables included amyloid burden, APOE4 status, sex, and education. Amyloid burden was assessed by 11C‐PiB and regional tau was assessed by 18F‐MK‐6240 PET. SUVR values representing tau accumulation were extracted using two MRI segmentation methods: (1) the FreeSurfer‐derived EC label, and (2) Automatic Segmentation of Hippocampal Subfields (ASHS)‐derived MTL subregions, including the EC and Brodmann areas 35 and 36 (Br35, Br36) defined in 1mm‐MNI space. Partial volume correction was applied to the motion‐corrected PET data.

Result

Tau burden in the right Br35, right Br36, and age were significant predictors of CDR‐SB scores, with the greatest proportion of variance explained when all three were included. The FreeSurfer‐labeled EC and other variables did not significantly contribute to the model. Right Br36 and age were significant predictors of MMSE while right Br36 and APOE4 status were significant predictors of the global cognition composite score, and right Br36 was a significant predictor of the memory composite score. Follow‐up analyses showed that addition of the FreeSurfer EC region did not significantly contribute to any of the models.

Conclusion

Quantifying tau burden in Br35 and Br36 better accounted for individual variability in cognition, when compared to standard EC labeling approaches. This suggests tau burden in these subregions may help identify CU and MCI individuals who are on a trajectory of decline due to AD.
Comparison of self‐similarity measures in FDG‐PET images and association with disease progression risk
Authors: Dicks Ellen , Barnard Leland R , Boeve Brad , Botha Hugo , Corriveau‐Lecavalier Nick , Graff‐Radford Jonathan , Gunter Jeffrey L. , Knopman David S. , Lee Jeyeon , Lowe Val J. , Schwarz Christopher G. , Senjem Matthew L. , Jack Clifford R. , Petersen Ronald C. , Jones David T.
Published: December 2023

Background

Decreased image self‐similarity of repeated FDG‐PET scans has been suggested to indicate increased risk for disease progression. Here, we compared several self‐similarity measures based on conventionally used voxel‐ and ROI‐based approaches and those based on patterns of cortical metabolism.

Method

From the MCSA/ADRC, we included 376 cognitively unimpaired (CU) individuals and those with a clinical diagnosis of MCI (n = 55) or AD (n = 20) who had two FDG‐PET images within 2‐3 years and clinical follow‐up available. We compared image self‐similarity for three approaches: voxel, ROI and “eigenbrain” (Fig.1). For the voxel approach, FDG‐PET images were normalized to template space, grey matter masked, and intensity normalized to the pons to create standard uptake value ratios (SUVR) for each voxel. From these images, mean SUVR were extracted for 122 ROIs (MCALT‐ADIR122) for the ROI approach. For the “eigenbrain” approach, the SUVR images were transformed to a latent space embedding composed of 253 components (“eigenbrains”) and reflecting metabolism patterns, that was generated in an independent sample of 7008 FDG‐PET images. For each approach, image self‐similarity between baseline and follow‐up values (voxel, ROI or eigenbrain) was determined using three metrics (Pearson correlation, cosine, Euclidean distance). We computed AUC to determine which approach and metric would best discriminate between groups. We used Cox regression analyses to assess whether the metrics could predict disease progression.

Result

Comparing each distance metric across approaches, AUC was highest in differentiating clinical diagnoses using self‐similarity measures based on eigenbrains, then voxels, then ROIs (e.g., Euclidean distance CU vs AD AUC eigenbrain: 0.86, voxel: 0.75, ROI: 0.71; Fig.1). Across all approaches, Euclidean distance always discriminated best between classes. Eigenbrain‐based Euclidean distance was associated with risk for progression to MCI in CU (HR [95%CI]: 1.25 [1.05, 1.49]), and eigenbrain‐based cosine and Euclidean distances were associated with risk for progression to AD in MCI (1.61 [1.1, 2.34] and 1.53 [1.01, 2.31], respectively), while we found no associations for voxel‐ or ROI‐based distance measures.

Conclusion

Eigenbrain‐based measures outperformed other, more conventional approaches in discriminating clinical diagnoses, and were associated with risk for disease progression. Our results suggest that decreased self‐similarity in metabolism patterns informs on disease stage and prognosis.
Age‐Dependent Changes in Perineuronal Nets and Associated Parvalbumin Interneurons in the 5xFAD Amyloidosis Mouse Model
Authors: Nelson Ruth S , Rangaraju Srikant , Rayaprolu Sruti , Kumar Prateek , Espinosa‐Garcia Claudia , Xiao Hailian
Published: December 2023

Background

Perineuronal nets (PNNs) are extracellular matrix structures that surround neurons and proximal dendrites and regulate synaptic transmission, plasticity, and several facets of memory. PNNs are commonly associated with parvalbumin‐positive (PV+) fast‐spiking interneurons which are hypothesized to play physiological roles in memory and cognition. Despite a growing literature related to PNNs and PV+ neurons’ roles in synaptic maintenance and memory, much remains unknown regarding how these structures are affected in neurodegenerative diseases such as Alzheimer’s Disease (AD). In this study, we used the 5xFAD amyloidosis mouse model to investigate how AD‐like pathology affects PNNs and PV+ neurons

Method

Using immunofluorescence microscopy, we stained 5xFAD and Wild Type (WT) mice at 1.8, 3, 6, and 10 months of age. We stained for PV+ neurons (using anti‐PV antibody), PNNs (using a WFA antibody), and for Amyloid‐Beta (Aβ) plaques (using a 4G8 antibody). Images were then processed using ImageJ to quantify the presence of PV+ neurons, PNNs, and the association between them in several regions of interest across genotypes and age groups.

Result

We found that PNNs, but not PV+ neurons, are significantly depleted in the anterior cortex, posterior cortex, and subiculum of the 5XFAD mice in early amyloidosis (3‐6 month old 5XFAD mice). Furthermore, analyses investigating the co‐localization of PNNs and PV+ neurons in these regions found that PNNs were depleted surrounding PV+ neurons in an age‐dependent manner in the 5XFAD mice compared to WT. Specifically, in early amyloidosis (3‐6 months) there was a general depletion of PNNs, but in later amyloidosis (6 ‐10 months) the depletion of PNNs was preferentially surrounding PV+ neurons. Finally, assessing the relationship between Aβ plaque proximity and the co‐localization between PNNs and PV+ neurons revealed that PNNs closer to Aβ plaques were more likely to be associated with PV+ neurons

Conclusion

Collectively, these findings may indicate the time‐dependent impact of Aβ pathology on PNNs, both in general and specifically surrounding PV+ neurons. Our ongoing studies will further characterize PNN and PV changes across a wider age spectrum.
Combined Digital Clock Drawing Test and Delayed Word Recall and their relationship with PET Amyloid Biomarker Status in Cognitively Unimpaired Older Adults
Authors: Jannati Ali , Thompson Karl , Banks Russell E , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. , Gomes‐Osman Joyce Rios , Showalter John , Tobyne Sean , Pascual‐Leone Alvaro
Published: December 2023

Background

DCTclock™ is an AI‐enabled digital cognitive assessment (DCA) that strongly discriminates between cognitively impaired and unimpaired individuals (receiver operating area under‐the‐curve AUC = 0.89). Among cognitively unimpaired individuals, DCTclock predicts greater PET Aβ burden and shows stronger discrimination (Cohen’s d = 0.76) between Aβ± individuals than the Preclinical Alzheimer’s Cognitive Composite (d = 0.30) (Rentz et al., 2021). The Digital Clock and Recall (DCR™) was recently created by adding 3‐word delayed recall to DCTclock to assess verbal memory impairment – an early hallmark of Alzheimer’s disease. We assessed whether recreating the DCR with the 3‐word delayed recall from the Mini‐Mental State Examination (MMSE) and DCTclock would improve classification of Aβ PET biomarker status among cognitively unimpaired older adults.

Method

DCTclock, MMSE (including delayed recall), and Aβ PET imaging data were collected from 159 cognitively unimpaired older adults in the Harvard Aging Brain Study (age = 78.6±5.9; 98 females; MMSE = 28.9±1.4). Logistic regression classifiers were trained to classify Aβ biomarker status and were assessed with standard metrics and AUC as compared to age‐ and MMSE‐only models.

Result

The best‐performing model classified biomarker status among cognitively unimpaired individuals with an AUC of 0.76 (sensitivity = 0.65, specificity = 0.73, accuracy = 0.71)‐outperforming age‐only and total MMSE‐only models (AUCs = 0.61). Recursive feature elimination identified spatial reasoning, average speed, maximum speed on Copy Clock, oscillatory motion on Command Clock, and delayed recall score as key features. DCTclock or recreated DCR summary scores alone classified biomarker status with AUCs of 0.72 and 0.74, respectively.

Conclusion

The DCR, which combines DCTclock with delayed verbal recall, may offer a means to classify Aβ biomarker status among cognitively unimpaired individuals in as little as 3 minutes. Classification models trained on a subset of DCR features performed better than all other models, including traditional neuropsychological testing. These results reinforce the potential for DCR solutions to streamline cognitive testing in the clinic and accelerate diagnosis for individuals with early‐stage Alzheimer’s and other dementias. Future work will examine the best possible combination of additional tests to further increase classification accuracy.
Multifaceted approach to minority recruitment for participants in Alzheimer’s Disease research studies
Authors: Boegel Amy R , Wilson Blake , Mendenhall Laura , Newhouse Paul
Published: December 2023

Background

Alzheimer’s Disease (AD) disproportionately affects Black and Hispanic adults as compared to white adults, yet 75% of those who participate in AD research are white (1,2,3). Without the full participation of under‐represented groups in clinical research studies and trials, researchers will have limited understanding of how potential treatments work in these communities (4,5).

Method

The study used an iterative, mixed methods approach to enhance the recruitment of URGs for AD research studies. These methods involved targeted direct mailing campaigns, advertising in minority specific media outlets (radio and newspaper), and URG‐specific email outreach. Each encounter offered an opportunity to address concerns and educate while also recruiting potential participants into AD research studies.

Direct mailings were sent to 15,200 under‐represented people (URPs) within a 25‐mile radius of Vanderbilt University Medical Center (VUMC). The direct mailing contained a letter to the URP and a study brochure. Each mailing was in an envelope containing the official VUMC logo. Two weeks after the direct mailing, weekly emails were sent to URPs from the direct mailing list. If there was no response to the email, a second email was sent 4 weeks later. There was a total of 492 URPs that responded, a return of 3.2%. As the number of URPs reaching out from the direct mailing began to slow, additional URP specific advertisements were conducted in minority specific media outlets (radio and newspaper).

Result

Preliminary results have shown that a mixed method approach has been successful in recruiting URGs. From August 2022 to April 2023 (8 months) from the direct mailing campaign, there were 93 URPs prescreened and 38 URPs that completed a screening visit. An additional 29 URPs were prescreened after the minority specific media outlets, and 5 were screened. In comparison, from 2017‐2021, only 18 URPs were prescreened and 6 enrolled into AD research studies.

Conclusion

Our findings show that, direct mailings campaigns can be a highly effective recruitment tool for URP recruitment into AD research studies. The success of the direct mailing campaign was enhanced by utilizing additional methods of contact with the targeted URPs.
Multilevel Racism and Discrimination and Cognitive Function and/or Cognitive Decline: A Systematic Review
Authors: Moody Danielle L. Beatty , Wright Regina Sims , Waldstein Shari R. , White Kellee , Taylor Antione D. , Maciver Peter , Tchangalova Nedelina , Pantesco Elizabeth J.
Published: December 2023

Background

Blacks experience the greatest burden of racism and are twice as likely to have Alzheimer’s or other dementias as Whites in addition to higher rates of cognitive decline which acts as an early warning sign for these clinical outcomes (Discrimination in America Report, 2018; Alzheimer’s Disease Facts & Figures, 2023). Examining the levels, types, and forms of racism and discrimination associated with cognitive functioning and decline is essential to clarify mechanistic pathways and aid opportunities for intervening upon racially disparate burdens in cognitive impairment and Alzheimer’s trajectories. This systematic review aimed to establish (a) relations of racism and discrimination to cognitive function and decline, (b) characterize these differences across the levels, types, and forms of racism and discrimination, and (c) detail these linkages across a comprehensive battery of cognitive endpoints, among community‐dwelling, neurologically healthy Black adults aged 18 and older.

Method

Using the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses protocol 2,997 studies were identified from searches in CINAHL, PsycINFO, PubMed, and Web of Science published until April 7, 2023. We included original empirical articles that examined any form of racism and racial discrimination and cognitive functioning or decline across Blacks. These endpoints included Alzheimer’s disease; cognitive change, decline, function, impairment, performance; cognition; delayed recall, dementia; episodic or working memory; recall; neuropsychological performance; executive function; and fluency among others. Two reviewers independently screened full‐text articles.

Result

We will present ongoing results and discuss the current state of knowledge, quality of existing studies, biopsychosocial pathways and gaps in the literature.

Conclusion

We will also highlight potentially key next steps.
Characterization of peripheral immune cell populations in stable and progressive Alzheimer’s disease
Authors: Loew Ethan B , Tracy Matthew , McCormick Beth , Haran John P
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common type of dementia which results in debilitating memory loss as the disease advances. In addition to the amyloid plaques, tau tangles, and neuronal inflammation characteristic of AD, there is strong evidence of dysregulation in the peripheral immune system, including decreased naïve T cells and increased memory T cells among older adults with AD. However, the involvement of the peripheral immune system in the neurodegenerative cascade leading to AD is poorly understood. Furthermore, among older adults with AD, some may experience rapid cognitive decline while others may maintain a stable cognitive status for years. It is currently unknown whether dysfunction in the peripheral immune system is associated with neuronal inflammation and cognitive decline.

Method

In our ongoing work, we are longitudinally characterizing resting peripheral immune system cells by flow cytometry and here present data from a subset of those with AD (n = 19) or no dementia (ND, n = 93) whom we have followed for >1 year.

Result

We have identified an increase in B cells (percent all lymphocytes, AD 6.4 (SD 8.6) vs ND 4.0 (SD 2.4) p = 0.031) and CD4+/CD62L+ naïve T cells (percent CD4+ lymphocytes, AD 33.4 (SD 18.4) vs ND 25.4 (SD 14.1) p = 0.034) among AD patients. Among the population of AD patients experiencing cognitive decline (n = 4) determined by increasing ADAS‐Cog score >6 points over one year compared to stable scores (n = 11), we have discovered a decrease in CD4+/CD62L+ naïve T cells (percent CD4+ lymphocytes, stable 33.9 (SD 14.5) vs declining 20.5 (SD 16.1) p = 0.049), increase in effector memory CD4+ T cells (percent CD4+ lymphocytes, stable 28.2 (SD 4.8) vs declining 47.0 (SD 6.5) p<0.001), and increase in B cells (percent all lymphocytes, stable 2.6 (SD 1.5) vs declining 5.3 (SD 1.8) p = 0.010), when compared to older adults with AD and stable cognitive status.

Conclusion

This longitudinal clinical study identifies changes in resting peripheral B and T cell populations in AD patients and among AD patients with cognitive decline.
Intra‐ and post‐procedural lumbar puncture symptoms in a sample of Black/African American, American Indian/Alaska Native, and White middle age older adults
Authors: Cole Aleshia , Van Hulle Carol A. , Eierman Allison C , Rovner Sarah , Chin Nathaniel A. , McLester‐Davis Lauren W. Y. , Johnson Sterling C , Bendlin Barbara B , Okonkwo Ozioma , Gleason Carey E. , Edwards Dorothy F. , Asthana Sanjay , Carlsson Cynthia M
Published: December 2023

Background

Cerebral spinal fluid (CSF) as a biomarker of Alzheimer’s disease (AD) is a helpful tool in diagnosing preclinical disease. While blood‐based biomarkers are becoming increasingly used for early detection, CSF collection is still necessary for validation of AD blood‐based biomarkers and for identification of biomarkers for other types of dementias, including those that commonly co‐occur with AD. Attitudes and beliefs surrounding lumbar punctures (LPs) vary, and differing techniques as well as side effect rates might dissuade both clinicians and participants from considering LPs as a viable biomarker option. The aim of this analysis was to examine intra‐ and post‐procedural symptoms of a specific technique for collecting CSF from adult volunteers enrolled in the Wisconsin Alzheimer’s Disease Research Center.

Method

LPs were performed on 587 volunteers using a standardized LP technique with atraumatic needle. Up to 22 milliliters of cerebral spinal fluid was obtained using gentle syringe aspiration of fluid. Clinician notes documenting the procedure were used to assess intra‐procedural symptoms. A follow‐up phone call the next day was used to evaluate any post‐procedural symptoms. The association between participant characteristics and LP intra‐procedural symptoms, post‐procedural symptoms, and LP success were tested using linear regression.

Result

The majority of participants did not report any intra‐procedural (59%) or post‐procedural (77%) symptoms. Being female was associated with experiencing increased intra‐procedural symptoms among Black / African American and White participants; younger age and lower waist‐to‐hip ratio were associated with higher rates of intra‐procedural symptoms among White participants. Participant characteristics were not associated with post‐procedural symptoms. LP success was high for all groups (67% to 90%). Among White participants, pain and vasovagal responses were associated with terminating the LP before sufficient fluid was collected. Among Black / African American participants, pain was associated with terminating the LP procedure before sufficient fluid was collected. Among American Indian / Alaska Native participants, no intra‐procedural symptoms were associated with early LP termination.

Conclusion

We provide rates of LP intra‐procedural and post‐procedural symptoms in a diverse sample of middle‐aged and older adults. These data suggest that LPs are safe and well tolerated across a diverse group of participants.