bluuebunny/crossref_metadata_2025 huggingface dataset:
Hearing symptom profiles in Alzheimer’s disease and frontotemporal dementia
Authors: Johnson Jeremy , Levett Benjamin , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Jiang Jessica , Bamiou Doris‐Eva , Hardy Chris JD , Warren Jason D
Published: December 2023

Background

Hearing loss has emerged as a marker of cognitive decline and potential treatment target in dementia, however the symptom profiles that characterise hearing impairment in different dementia syndromes are poorly characterised. Beyond sound detection, these diseases impair aspects of auditory perception that are crucial for communication in daily life. Here we addressed changes in everyday hearing function in Alzheimer’s disease and frontotemporal dementia syndromes, using standardised auditory symptom questionnaires completed by patients’ caregivers.

Method

Primary caregivers for patients with Alzheimer’s disease (n = 20), logopenic variant primary progressive aphasia (n = 8), nonfluent variant primary progressive aphasia (n = 13), semantic variant primary progressive aphasia (n = 13) and behavioural variant frontotemporal dementia (n = 18) completed the Hearing Impairment Impact – Significant Other Profile, adapted Amsterdam Inventory for Auditory Disability and Khalfa Hyperacusis questionnaires. The Amsterdam Inventory for Auditory Disability was also completed by 15 healthy age‐matched individuals. No participant had a past history of significant otological disease.

Result

Scores on the Hearing Impairment Impact – Significant Other Profile and Khalfa Hyperacusis Questionnaire respectively demonstrated greater carer burden and increased sensitivity to sound in the behavioural variant frontotemporal dementia group compared with the Alzheimer’s disease group. On the Amsterdam Inventory for Auditory Disability, multi‐domain hearing difficulties were endorsed for the behavioural variant frontotemporal dementia and primary progressive aphasia groups relative to healthy controls, and total scores in the logopenic and semantic variant primary progressive aphasia groups were significantly worse than both the healthy control and Alzheimer’s disease groups. Syndromic groups showed differentiable hearing profiles across hearing domains.

Conclusion

Major dementia syndromes have distinct profiles of everyday hearing difficulty, and patients with frontotemporal dementia and progressive aphasia syndromes may have particularly marked (albeit often unrecognised) changes in their hearing. These findings should motivate the development of bespoke auditory tests to assess central hearing function and personalised hearing management strategies in these diseases.
The Antidepressant Therapy Selective Norepinephrine Reuptake Inhibitors (SNRIs) Reduces the Risk of Alzheimer’s Disease
Authors: Cortes‐Flores Helena , Torrandell‐Haro Georgina , Brinton Roberta Diaz
Published: December 2023

Background

Depression has been established as a risk factor for developing Alzheimer’s Disease (AD). Further, depression is a common symptom of the prodromal phase of the disease and acts as an accelerating factor for cognitive decline before and after dementia diagnosis. Based on this association, analyses of real‐world medical data were conducted to determine the impact of anti‐depressive pharmacological therapy, Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), on risk of AD diagnosis. This study aimed to determine the effect of SNRI therapy on AD incidence, as well as determining responder vs non‐responder phenotypes on demographic characteristics, comorbidity burden, and co‐treatment profile.

Method

A retrospective analysis was conducted using the Mariner insurance claims dataset and included patients 60 years of age and older with a diagnosis of depression. To minimize bias, a propensity score matching was conducted to adjust for age, gender, cci and comorbidities. The propensity score matched population was surveyed for a diagnosis of AD after at least 1 year of SNRI drug exposure, and different durations of SNRI therapy were analyzed. Responders were detected through sensitivity analyses based on comorbidities and drug combinations.

Result

The propensity score matched group included 307,671 patients exposed to SNRIs and 307,671 patients with no exposure to any antidepressant therapy. SNRI therapy was associated with a significant decrease in risk of AD diagnosis (RR [95%CI]: 0.73 [0.70–0.76]; P<.0001), with women (RR [95%CI]: 0.66 [0.63–0.70]; P<.0001) exhibiting greater risk reduction compared to men (RR [95%CI]: 0.88 [0.82–0.95]; P<.0001). Long‐term SNRI treatment (>6 years) was associated with the greatest AD risk reduction (RR [95%CI]: 0.50 [0.47–0.53]; P<.0001). Responders exhibited higher incidence of obesity and greater use of anti‐inflammatories.

Conclusion

SNRI therapy was associated with a significant reduction in AD risk. Furthermore, increased duration of SNRI therapy was associated with greater AD risk reduction. Responders displayed fewer comorbidities and co‐treatments although they had a higher incidence of obesity. Clinically, these findings, based on real‐world psychiatric care, provide data regarding long‐term neurological health outcomes of SNRI anti‐depressant therapy. From a mechanistic perspective, data reported herein indicate that sustaining noradrenergic function is a key pathway involved in preventing AD.
Towards the future of ADRD diagnosis: combination of a brief digital cognitive battery and plasma biomarkers for diagnosis and prognosis of disease
Authors: Tsoy Elena , VandeVrede Lawren , La Joie Renaud , Rodriguez Anne‐Marie , Windon Charles , Smith Karen , Dilworth‐Anderson Peggye , Rabinovici Gil D. , Possin Katherine
Published: December 2023

Background

Scalable and accurate diagnostic markers of Alzheimer’s disease and related dementias (ADRD) are urgently needed. A combination of a sensitive brief digital cognitive assessment and plasma biomarkers could represent a promising scalable alternative to standard diagnostic procedures. We evaluated the performance of the TabCAT Brain Health Assessment Cognitive Score (BHA‐CS) and plasma Aβ42/40, pTau‐181, NfL, and GFAP at predicting concurrent Aβ positivity on CSF or PET, concurrent disease severity, and future functional decline.

Method

Participants were 309 subjectively or objectively impaired older adults enrolled in longitudinal observational studies at UCSF (Table 1), who completed a blood draw and TabCAT‐BHA at baseline. Biomarker concentrations were measured using commercially available Quanterix kits. Receiver operating characteristic analyses were used to determine the accuracy of combined BHA‐CS and plasma biomarkers in discriminating between Aβ+/‐ status on CSF/PET at baseline. Multiple regressions were used to examine baseline associations of BHA‐CS and plasma markers with disease severity measured by Clinical Dementia Rating Sum of Boxes (CDR‐SB). Linear mixed effect models were used to examine the associations of baseline BHA‐CS and biomarker values with longitudinal decline on CDR‐SB. All analyses controlled for age, sex, education, and baseline diagnosis.

Result

pTau‐181 was the strongest predictor of Aβ positivity (AUC = .745; 95%CI: .656‐.833), with no significant improvements in the AUC with the addition of any combination of markers (Figure 1). In a combined model with all markers included simultaneously, BHA‐CS (B = ‐0.678, P<.001) and plasma NfL (B = 0.625, P = .01) were the only unique significant predictors of concurrent CDR‐SB. In a combined mixed model with all markers included simultaneously, baseline BHA‐CS, pTau‐181, NfL, and GFAP were unique significant predictors of CDR‐SB decline (Figure 2), and together accounted for 27% of longitudinal variance in CDR‐SB.

Conclusion

Our findings indicate unique and complementary roles of scalable digital cognitive and plasma biomarkers as diagnostic and prognostic markers of ADRD. At baseline, whereas pTau‐181 was most accurate at predicting Aβ positivity, a combination of BHA‐CS and NfL was most accurate at predicting concurrent disease severity. In longitudinal analyses, a model that combined baseline cognitive testing results and plasma pTau‐181, NfL, and GFAP was most accurate at predicting future decline.
Relationships between neuroimaging parameters, APOE genotypes and composite scores for memory, executive functioning and language from the National Alzheimer’s Coordinating Center (NACC)
Authors: Lee Michael L. , Scollard Phoebe , Gibbons Laura E , Mukherjee Shubhabrata , Choi Seo‐Eun , Klinedinst Brandon S , Trittschuh Emily H. , Mez Jesse B. , Saykin Andrew J. , Dumitrescu Logan C , Kukull Walter A. , Hohman Timothy J. , Crane Paul K
Published: December 2023

Background

We harmonized composite scores for memory, executive functioning (EF), and language from granular cognitive data from the National Alzheimer’s Coordinating Center (NACC) uniform dataset on 39,965 individuals. We explored if our cognitive scores correlated with APOE genotype and structural magnetic resonance imaging data.

Method

In our previously published harmonization methods we used confirmatory factor analysis models, guided by theoretical considerations from content experts, to estimate domain scores. For this cross‐sectional analysis of last visits in participants over age 60, we obtained APOE genotype data (n = 28,558 individuals) and FreeSurfer regional volume data (n = 2,404 individuals). We looked at relationship between cognitive performance and APOE genotype grouping by disease group (normal cognition, mild cognitive impairment (MCI), or AD dementia). We ran student’s two sample t‐test to assess the effect of APOE ε4 genotype on cognitive domain score. We also ran regression models for cognitive domain scores on each FreeSurfer region selected a priori on the basis of assumed association on that index domain adjusting for age, gender and APOE genotype.

Result

Relevant demographic and clinical data are summarized in Table 1. Associations with APOE genotype and each cognitive domain are shown in Figure 1. As expected, participants with at least one APOE ε4 alleles compared with none had lower composite memory scores (p<0.01, t‐test) compared with those with none in participants with dementia and MCI. APOE ε4 carriers also had lower language scores in participants with dementia (p = 0.037, t‐test). Among the FreeSurfer regions, composite memory scores were strongly associated with hippocampal volume, parahippocampus and entorhinal cortex thickness across all dementia categories (Table 2). EF scores were associated with 2 EF brain regions of interest in participants with dementia. Language scores were associated with 2 language regions of interest in participants with dementia.

Conclusion

Our analyses shows composite scores are associated with APOE genotype in participants with dementia and relevant brain regions in the memory domain across all dementia categories. Our analyses shows that our cognitive scores correlate with memory brain regions and APOE genotype in expected directions.
Sepsis as a risk factor for Alzheimer’s disease pathophysiology
Authors: Giridharan Vijayasree V , Catumbela Celso , Catalão Carlos Henrique V R. , Ganesh Bhanu Priya , Petronilho Fabricia , Dal‐Pizzol Felipe , Morales Rodrigo , Barichello Tatiana
Published: December 2023

Background

The sepsis‐induced polymicrobial infection leads to life‐threatening organ dysfunction that accounts for high mortality and morbidity worldwide. More than half of those who survive sepsis have a worse quality of life and long‐term cognitive deficits. Significant alteration of gut microbiota has been documented in sepsis patients, impacting both compositional and functional levels. In this context, we aimed to explore the cross‐link between the gut‐brain axis on sepsis‐induced long‐term cognitive decline using Alzheimer’s disease mouse model.

Method

Male, 50‐day‐old APP/PS1 mice were subjected to a gold standard sepsis model by cecal ligation and perforation (CLP) surgery to induce sepsis or sham surgery as a control group. Longitudinally, at 3, 30, and 120 days after sepsis or sham surgery, feces were collected for 16S rRNA sequencing and short‐chain fatty acids (SCFAs) evaluation. The gut was collected for histology, mucin, and amyloid‐beta (Aβ) staining. The brain was collected to measure inflammatory mediators, neuroinflammatory markers (IBA‐1 and GFAP), and soluble and insoluble Aβ. Assessment of cognition was performed using novel object recognition (NOR) at 30 and 120 days after sepsis.

Result

Sepsis mice demonstrated an altered microbiome measured by alpha diversity, beta diversity, and relative abundance at 30 and 120 days. In the long‐term after sepsis, SCFAs were reduced, villi length and crypt depth decreased, and fucosylated goblet cells were significantly reduced in sepsis mice demonstrating gut dysfunction. However, no positive signal for Aβ was observed in the gut. In the brain, at 30 and 120 days, proinflammatory cytokines were increased in PFC, and decreased anti‐inflammatory cytokines in the hippocampus were observed. The neuroinflammation after infection was verified by measuring the glial cell activation. Compared to the age‐matched control, sepsis mice elevated Aβ burden at 120 days after surgery. Further, after CLP surgery, long‐term mice demonstrated a significant reduction in the recognition index in the NOR task.

Conclusion

Sepsis‐induced enteric dysbiosis, gut modulation, increased brain inflammatory cytokines, and insoluble Aβ levels negatively regulated the cognitive behavior in APP/PS1 mice. Therefore, gut microbiota can be modified to impact the sepsis‐induced long‐term cognitive decline in sepsis survivors positively.
Distinct immune signatures associated with sex and genotype in the 12m novel hAPP hAPOE mouse risk model of Alzheimer’s disease
Authors: Van Rossum Hannah , Delatorre Nicole , Brinton Roberta Diaz
Published: December 2023

Background

Understanding the biology of model systems is critically important in the identification of biomarkers to delay or prevent Alzheimer’s disease. Previous findings in our group demonstrate sex differences in immune transcripts in the AD brain and in the humanized apolipoprotein E (APOE) mouse risk model. With this study, we extend these discoveries to further investigate the effect of APOE genotype using a novel risk mouse model with humanized amyloid precursor protein (APP) and humanized‐APOE transgenes (Jackson Laboratory). We test the hypothesis that during midlife aging, hAPP hAPOE ε4/4 genotype, and female sex will show increased risk profiles for Aβ 42:40 ratio and immunophenotypes associated with Alzheimer’s disease.

Method

To identify midlife (12 months; human correlate 44 years) immunophenotypes that may contribute to AD 3 different risk genotypes were studied: hAPP (6 male /6 female), hAPP hAPOE ε3/3 (16 male/16 female), and hAPP hAPOE ε4/4 (16 male /16 female). The left hemisphere of the brain was collected and prepared for multi‐color flow cytometry. Microglial reactivity (MHCII, CD68), phagocytosis (pHrodo), oxidative stress (CellRox), and the presence of lymphocytes (CD3, CD4, CD8, CD19) were determined. Peripheral blood was collected and assessed for monocytes and lymphocytes while plasma was isolated and ELISA was used to detect the presence of Aβ 40‐42, and levels of pro‐inflammatory cytokines. Female animals were monitored daily by lavage to determine midlife endocrine status.

Result

hAPP hAPOE ε4/4 animals demonstrated accelerated endocrine aging compared to hAPP hAPOE ε3/3 animals. Plasma beta‐amyloid 42:40 ratio, and levels of IL‐1B, and IL‐6 showed a significant interaction between sex and hAPP hAPOE genotype (p<0.05, p<0.05, p<0.05). Plasma levels of IL‐5 and CXCL1 trended toward genotype significance with p = 0.0544 and p = 0.0556, respectively. Percentage of MHCII+ activated microglia was significantly impacted by sex (p = 0.0005) and by genotype (p<0.0001).

Conclusion

The interaction between hAPP and hAPOE genotype, in coordination with biological sex significantly impacts immunophenotypes of the CNS and periphery during midlife aging. Precision interventions targeting sex and genotype‐dependent prodromal immune biomarkers may serve as an opportunity to support homeostatic immune milieu or to modulate harmful inflammatory signaling and reduce risk of AD or delay AD onset.
Development and comprehensive evaluation of high‐resolution 0.5 mm isotropic T2‐weighted, PD‐weighted, T2 map and FLAIR templates of the MIITRA atlas.
Authors: Ridwan Abdur Raquib , Niaz Mohammad Rakeen , Wu Yingjuan , Zhang Shengwei , Bennett David A. A , Arfanakis Konstantinos
Published: December 2023

Background

Voxel‐wise, disease‐monitoring and other MRI investigations involving T2‐weighted(T2w), PD‐weighted(PDw), T2 map and FLAIR templates typically utilize young adult templates such as those of the ICBM atlas. Moreover, a comprehensive assessment of how such available standardized templates perform on aging population has not yet been performed. Here, a high‐resolution older‐adult population based T2w, PDw T2 map and FLAIR templates of the MIITRA atlas was developed using theories of super‐resolution and sparse‐representation and compared to other available standardized templates in terms of image quality, spatial normalization accuracy and representativeness of the older adult brain.

Method

T1‐weighted MPRAGE of isotropic 1mm resolution, five spin‐echo(0.5×0.5×0.5 mm3,TE = 20,40,60,80,100ms) and FLAIR data (0.5×0.5×4 mm3) were collected on 3T MRI scanners for 400 non‐demented older adults (50% male; 65‐95 years of age, 54% white and 43% black) participating in the construction of the MIITRA atlas. The subject T2 maps and PD‐weighted data were computed by fitting the T2 decay equation. The template construction technique involved upsampling the images to 0.5×0.5×0.5 mm3 using non‐local upsampling, and converting the T2‐weighted(TE = 60ms) to synthetic T1‐weighted, followed by linear registration to upsampled T1‐weighted data using ANTs. Next, the resulting transformations concatenated with the combined iterative T1w and DTI driven MIITRA atlas deformations were used to forward map each participant to exact physical locations in the MIITRA space. Finally, sparse representation data fusion technique was utilized on the transformed signals to construct the templates at isotropic 0.5mm resolution (Figure.1). MIITRA third echo T2‐weighted and FLAIR template was compared to available standardized templates (Figure. 2) in terms of inter‐subject spatial normalization accuracy when used for spatial normalization of 400 ADNI T2‐weighted and FLAIR participants respectively.

Result

The T2‐weighted and FLAIR templates of the MIITRA atlas exhibited higher image sharpness exemplified by higher spatial frequency content of the normalized power spectra(Figure. 2). MIITRA templates demonstrated higher inter‐subject spatial normalization accuracy and required the least deformations for spatial normalization of ADNI data(Figure. 3)

Conclusion

The new T2w, PDw, and FLAIR templates of the MIITRA atlas exhibited superior image quality, required lower deformations, facilitating higher spatial normalization accuracy for use in studies on older adults such as the ADNI datasets.
Machine‐learning based classification of Frontotemporal dementia in electronic health records for genetic discovery
Authors: Below Jennifer E. , Shaw Douglas , Evans Grahame , Baker James T , Bohlender Ryan J , Petty Alex , Petty Lauren E , Roshani Rashedeh , Lifferth Jonathan , Bastarache Lisa , Naj Adam C. , Bush William S. , Darby Ryan , McMillan Corey T , Samuels David , Huff Chad D
Published: December 2023

Background

Frontotemporal dementia (FTD) is a neurodegenerative syndrome characterized by distinct subtypes, each with unique clinical presentations and varying neuropathologic features. Although FTD is highly heritable, it is frequently undiagnosed and genetic causes of FTD are rarely determined, limiting what is known about the medical phenome associated with FTD. Here, we perform a combination of innovative strategies to improve detection of FTD in a large electronic health record (EHR) using machine‐learning (ML) and uncover genetic factors for FTD.

Method

123 FTD cases and 615 matched controls were identified via diagnostic codes and confirmed by manual expert review of medical notes in Vanderbilt University Medical Center’s (VUMC) EHR. We then applied a feature selection algorithm which calculated the frequency for each phecode within a randomly generated and demographically matched control set. A p‐value denoting the enrichment of each phecode was calculated based on the observed phecode frequency relative to the permutation‐derived null distribution. 28 phecodes were enriched in FTD cases compared to controls. Top predictors included “Neurological disorders”, “Memory loss”, Aphasia”, and “Parkinson’s disorder”. We then developed a classification and regression tree model that leveraged enriched phecodes to label an undiagnosed case set in VUMC’s EHR‐linked DNA databank, BioVU. The model was trained on 96 cases and 481 controls, with 28 cases and 139 controls reserved for testing.

Result

Of the testing set, 19 of the FTD cases were classified as cases and 5 were misclassified as controls. 135 controls were classified as such and 4 were misclassified as cases, indicating 82% PPV. Application of this model in BioVU resulted in an expanded case set of inferred FTD, which is currently being leveraged in genomic analyses to identify causal variants. We have identified a genomic segment on chromosome 1 (146.9MB‐147.3MB) spanning ACP6 and GJA5 that is shared in significant excess among FTD cases. These genes have been associated with intellectual disability, aphasia, and autism.

Conclusion

Our results demonstrate both the potential of machine learning‐based approaches for case acquisition in dementia subtypes that are often underdiagnosed in medical record databases and illustrate how inferred cases can be leveraged for novel gene discovery.
Informant‐ and Patient‐reported Subjective Cognitive Decline: a preliminary analysis of the Brazilian Subjective Cognitive Decline Cohort
Authors: De Souza Haniel Bispo , Souza Victória Tizeli , Giordani Manuella Edler Zandoná , da Mota Simone Sieben , De Marchi Bruno De Oliveira , Formoso Carolina Rodrigues , Rivas Gabriela Raquel Paz , Carvalho Guilherme Da Silva , Beltrami Lucas Bastos , Santos Rhaná Carolina , Suwa Samuel Masao , Slaviero Wesley , de Albuquerque Ana Letícia Amorim , Strelow Matheus Zschornack , Carello‐Collar Giovanna , Chaves Marcia L Fagundes , Zimmer Eduardo R , Castilhos Raphael Machado
Published: December 2023

Background

Subjective Cognitive Decline (SCD) is characterized by self‐experience of deterioration in cognitive performance in cognitive unimpaired (CU) individuals and may represent a preclinical stage of neurodegenerative diseases, especially Alzheimer’s disease (AD). Informant‐reported cognitive complaints appear to increase the risk for cognitive decline in SCD individuals. We aimed to describe a preliminary analysis of informant‐ and patient‐reported SCD in the ongoing Brazilian SCD (BRASCODE) Cohort.

Method

We are evaluating CU individuals older than 65 years‐old with cognitive complaints (and at least one SCD‐plus criteria). Biofluid‐ and imaging‐based biomarkers are being performed. Here, we evaluated the concordance of complaints between patients/informants and correlated them with patient’s sociodemographic and clinical variables. We described continuous variables as median (interquartile range, IQR) and categorical as frequencies. We performed a linear regression analysis with informant‐related complaints as the dependent variable, measured by the Subjective Cognitive Decline Scale, that ranges from 0 to 14, with scores ≥ 7 indicating complaint.

Result

Between March and November 2022, 52 SCD patients were included, 70 (68‐73) years of age, 73.1% (n = 38) women. The median SCD‐patient and SCD‐informant scale was 8.5 (7 ‐ 9.25) and 5 (3 ‐ 7.25), respectively. The minority (20, 38.5%) of the informants agreed with the patients' cognitive complaints. The patients had a median of 3 (2 ‐ 4) SCD‐plus criteria, mainly age at onset of SCD ≥ 60 years‐old (16, 80%) and concerns associated with SCD (15, 75%) (Table 1). The SCD‐patient scale correlated negatively with patient age (rho = ‐ 0.362; p‐value = 0.008) and the SCD‐informant scale correlated negatively with patient education (rho = ‐ 0.349; p‐value = 0.01). In the linear regression analysis, the SCD‐informant scale was associated with the patient’s black race and education (p = 0.00141) (Table 2).

Conclusion

In the ongoing BRASCODE cohort, the preliminary baseline analysis showed that most informants did not agree with the patients complaints, but education and race seem to influence the informant’s complaints. The increase in the sample size, AD biomarkers analysis, and follow‐up may bring valuable information about the relationship between patient’s and informant’s complaints.
Determinants of Changes in the Clinical Dementia Rating Scale: Reversion and Conversion
Authors: Wilks Hannah M , Cruchaga Carlos , Fagan Anne M. , Schindler Suzanne E. , Morris John C , Hassenstab Jason J.
Published: December 2023

Background

At the Knight Alzheimer Disease Research Center (ADRC), clinicians are blinded to cognitive data and prior assessments to ensure that ratings are free of circularity and examiner bias. It is common for cognitive status to fluctuate between normal and abnormal in longitudinal studies of aging and dementia, even when using the gold standard Clinical Dementia Rating (CDRâ) scale. CDR fluctuation is common when clinical symptoms are mild. It was hypothesized reverters, defined as individuals who change from CDR 0.5 to CDR 0, would have worse cognition, more abnormal biomarkers, and more likely to progress to CDR>0 compared to participants who remain unimpaired (“CN").

Method

Cognitively normal participants with at least three annual visits were included (n = 924, Table 1). Participants were classified as CN, reverters, and converters to stable dementia (“converters”). The Knight PACC was used to compare cognition between groups. Participants (n = 187) with cerebrospinal fluid or positron imaging tomography biomarkers were classified as amyloid “positive” or “negative”. The visit of first CDR>0 was defined as the “index visit” and the visit prior was defined as the “pre‐index visit.” Linear models evaluated relationships between biomarker status, APOE ε4 status, and cognition at the pre‐index and index visit. Logistic regression evaluated predictors of converting to a dementia status (“conversion”) and reverting from CDR 0.5 back to CDR 0 (“reversion”).

Result

Of 924 participants, 127 (14%) were reverters and 142 (15%) were converters. Converters had the lowest PACC scores of the three groups at the pre‐index and index visit, with reverters having slightly better PACC scores than converters but significantly worse scores than CN (Figure 1). Predictors of conversion and reversion included older age, male gender, APOE ε4 carriage, and worse PACC scores. Amyloid positivity did not predict conversion or reversion. Reverters exhibited more longitudinal cognitive decline compared to CN but the magnitude of decline was less than converters (Figure 2).

Conclusion

CDR reversion is a risk factor for future conversion to CDR>0 and is associated with older age, APOE ε4 carriage, and poor cognitive performance. CDR reversion appears to occupy a transitional phase in disease progression between cognitive stability and consistent progression to stable dementia.
GM‐CSF Treatment Increases the Number of Purkinje Cells in a Mouse Model of Down Syndrome
Authors: Ahmed Md. Mahiuddin , Aghili Leila , Wang Athena Ching‐Jung , Elos Mihret , Boyd Timothy D. , Chial Heidi J , Potter Huntington
Published: December 2023

Background

Down syndrome (DS), the most common chromosomal disorder that is a genetic cause of intellectual disability (ID), is characterized by mild‐to‐severe cognitive deficits and several neurological and brain anatomical abnormalities in people with DS and in animal models of DS. Among them, a marked reduction in the volume of the cerebellum has been reported in fetuses, newborns, and adults with DS, and in mouse models of DS. It has been well documented that children and adults with DS display motor deficits consistent with cerebellar abnormalities. Growing evidence suggests that the cerebellum is involved in the processing of cognitive functions. Reduced size of the cerebellum may be one of the underlying causes of cognitive deficits in DS. However, the cellular functions of the cerebellum remain poorly understood in people with DS. The beneficial effects of treatment with the hematopoietic growth factor granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) in animal models of DS, Alzheimer’s disease (AD), normal aging, and clinical trials of AD subjects suggest that it may serve as a potential therapeutic for these disorders. Our recent published data showed that treatment with GM‐CSF rescues the cognitive impairments and improves hippocampal pathology in Dp16 mice. To elucidate cerebellum‐associated cellular functions, we investigated purkinje cell pathology in aged male Dp16 mice after treatment with GM‐CSF compared to saline‐injected mice.

Method

We injected 12‐ to 14‐month‐old male Dp16 male mice subcutaneously with GM‐CSF (5 mg/day; 5 days/week) or with saline (200 ml) for 24 injections total over 29 days. On day 29, the brains were fixed, and tissues were processed for immunohistochemistry.

Result

We observed a reduced number of parvalbumin‐positive purkinje cells and loss of arborization in the cerebellum of male Dp16 mice compared to wild‐type littermates. Treatment with GM‐CSF significantly increased the number of parvalbumin‐positive purkinje cells and partially restored dendritic arborization in the cerebellum of Dp16 mice compared to saline‐injected mice.

Conclusion

Our results suggest that treatment with GM‐CSF improves cellular abnormalities by increasing the number of purkinje cells in the cerebellum of Dp16 mice. Taken together with our previous results, these findings provide further evidence that GM‐CSF/sargramostim may have therapeutic benefits in people with DS.
Associations between aerobic fitness and subsequent memory performance in non‐demented Presenilin‐1 E280A mutation carriers: A preliminary report from the Colombia‐Boston longitudinal biomarker study
Authors: Guzman‐Velez Edmarie , Fabrega‐Ching Sofia , Oliveira Gabriel , Baena Ana Y. , Martinez Jairo E. , Vila‐Castelar Clara , Noriega Daisy , Munera Diana , Lopera Francisco , Quiroz Yakeel T.
Published: December 2023

Background

Greater aerobic fitness, objectively measured by VO2‐max, is considered a critical component of overall health and a strong predictor of cognitive functioning. It has been associated with less neurodegeneration in Alzheimer’s disease (AD) and greater functional brain connectivity and plasticity in healthy older adults. Yet, less is known about how it relates to AD progression in people at increased risk for dementia. In this study, we examined whether VO2‐max predicted memory decline in non‐demented mutation carriers and non‐carriers from a Colombian kindred with autosomal dominant AD (ADAD), and hypothesized that those with greater VO2‐max levels would exhibit slower cognitive decline.

Methods

12 Presenilin‐1 E280A mutation carriers (ages: μ = 39.61 years, SD:4.18) and 14 non‐carriers (ages: μ = 37.11 years, SD:6.59) underwent a standard graded maximal exercise test performed on a treadmill to assess their VO2‐max, which is the maximal rate of oxygen consumption during exercise, measured in milliliters of oxygen per minute per kilogram body mass. Participants also completed the CERAD word list learning and delayed recall, a measure of episodic memory, at baseline and again 18‐24 months later. Group differences were tested using the Mann‐Whitney U test. Linear mixed models were used to examine associations among baseline VO2 max and changes in CERAD word list test scores.

Results

VO2‐max levels did not differ between groups (p = .16). Compared to mutation non‐carriers, mutation carriers performed worse in word list learning (p = .008) and recall (p<.001) at baseline. VO2‐max levels were not associated with baseline word list learning (non‐carriers: p = .93; carriers: p = .76) or recall scores (non‐carriers: p = .82; carriers: p = .63). Baseline VO2‐max levels did not predict change in word list learning (non‐carriers: p = .47; carriers: p = .85) or recall scores (non‐carriers: p = .70; carriers: p = .87).

Conclusion

Preliminary findings suggest that aerobic fitness, which can be increased with exercise and is associated with greater health, does not relate to memory decline in preclinical ADAD. This is an ongoing longitudinal study, and we will continue to collect more physical activity data in this kindred to characterize these associations better. More research with larger samples is needed to elucidate whether physical activity could help delay AD progression regardless of aerobic fitness levels.
Fatigue Interacts with Amyloid Status To Predict Daily Working Memory Performance in Preclinical Alzheimer’s Disease
Authors: De Vito Alyssa N. , Kunicki Zachary J. , Emrani Sheina , Strenger Jennifer , Harrington Karra D , Roque Nelson A , Sliwinski Martin J. , Salloway Stephen , Correia Stephen , Thompson Louisa I
Published: December 2023

Background

Smartphone‐based cognitive assessment has the potential to reduce barriers to cognitive screening and increase sensitivity to detect preclinical Alzheimer’s disease (AD). Ecological momentary assessment of cognition is novel, and it is not yet well understood how psychological factors (i.e., mood, stress, and fatigue) may impact cognitive performance in remote, real‐world settings. We aimed to evaluate whether psychological factors influence daily cognitive performance differently between older adults with and without AD‐related pathologic change.

Method

Participants (N = 73) were cognitively unimpaired adults aged 60‐80 years (71% female, 89% White, 16.5 mean years of education) recruited for a digital cognitive assessment study. Participants had amyloid (Aβ) PET imaging results available from prior research participation [(n = 25 Aβ positive (Aβ+) and n = 48 Aβ negative (Aβ‐)]. A modified Telephone Interview for Cognitive Status (TICSm) score of ≥34 was used to indicate normal cognition. Participants completed 8 consecutive days of cognitive assessment using Mobile Monitoring of Cognitive Change (M2C2), a smartphone‐based testing platform developed as part of the National Institute of Aging’s Mobile Toolbox. Brief (i.e., 3‐4 minute) M2C2 sessions were assigned three times daily (morning, afternoon, and evening). Tasks included measures of visual working memory (WM, “Color shapes”), processing speed (PS, “Symbol search”), and episodic memory (EM, “Prices”). Multilevel modeling was used to examine the impact of self‐reported mood, stress, fatigue, and Aβ status on daily cognitive performance while controlling for age, sex, education, and time of day.

Result

Daily fatigue was found to interact with amyloid status such that Aβ+ individuals performed worse on the WM task when experiencing higher levels of fatigue (Est. = .004, p = .01) Higher levels of daily stress were associated with poorer performance on the PS task (Est. = ‐.0005, p = .03) but no interaction with Aβ status was observed. There were no significant relationships between mood and cognitive performance.

Conclusion

We demonstrated that psychological factors including fatigue and stress may impact performance on remote cognitive assessments. Results also suggested that fatigue may impact daily cognitive performance more among those with AD pathological change. These preliminary results suggest that psychological factors should be considered when determining optimal windows for remote cognitive screening.
Time of day cognitive performance differences in remote, self‐administered assessments and its association with cerebral amyloidosis
Authors: Strenger Jennifer , Emrani Sheina , Kunicki Zachary J. , Harrington Karra D , Roque Nelson A , Sliwinski Martin J. , Salloway Stephen , Correia Stephen , Thompson Louisa I
Published: December 2023

Background

Time of day (TOD) is known to potentially influence cognition in healthy older adults. Smartphone‐based ‘burst’ testing approaches are increasingly used in AD clinical research to assess cognition across multiple timepoints. This repeated assessment approach can therefore potentially help us understand how TOD may affect different domains of cognitive functioning in normal aging and AD. This study examined the effect of TOD, and its potential interactions with cerebral amyloidosis (Aß), on remote, smartphone‐based cognitive assessment performance.

Method

We recruited 73 cognitively normal adults with elevated (Aß+, n = 25) and non‐elevated (Aß‐, n = 48) Aß positron emission tomography (PET) status from the Butler Hospital Alzheimer’s Prevention Registry (mean age = 69.29, education = 16.45, 71.2% female, 89.0% White). Participants completed brief cognitive testing sessions 3x per day for 8 days using a mobile app. We used ANOVA to examine potential differences in performance on multiple cognitive tasks by TOD (see Table 1), and linear mixed models (adjusted for age, education, and session number) to determine how TOD, Aß status, and their interaction may predict episodic memory (EM) and processing speed (PS) performance.

Result

There were main effects of both Aß status and TOD on EM, with worse performance in the Aß+ group in the afternoon (p < .10 level; Est. = ‐0.05, SE = .02, p = .07), and in the evening (Est = ‐0.02, SE = .01, p = .02) relative to morning. A main effect of TOD on PS was also observed (Est. = ‐92.72, SE = 22.10, p < .001). Additionally, we found an interaction between Aß status and afternoon TOD on PS (Est. = 131.05, SE = 37.76, p < .001).

Conclusion

These findings suggest older adults may perform worse on episodic memory tasks in the evening, regardless of Aß status. Effect of TOD on PS varied by Aß status, with Aß+ individuals performing worse in the afternoon, and Aß‐ individuals performing better in the afternoon, relative to morning. While further validation is needed, these results suggest time of day is a significant factor in remote cognitive test performance and may be moderated by AD‐related pathology.
Validation of high resolution subcortical MRI signal using voxel to voxel histology to neuroimaging correlation in AD continuum: advancing neuroimaging biomarker tools for early AD staging
Authors: LaMore Tia , Huang Shuo , Chen Yuheng , Li Song Hua , Lee Wing Hung , Carreira Luzia Lima , Heinsen Helmut , Otaduy Maria Concepción Gracía , Shi Yonggang , Grinberg Lea T.
Published: December 2023

Background

Studies suggest a decrease in LC volume by 8% each Braak stage, starting at Braak 0‐1, while in normal aging the LC volume remains intact. Thus, LC volumetry is an attractive potential biomarker to monitor AD progression from precognitive stages. However, precise LC volumetry neuroimaging is challenging due to the LC’s small size and location in the brainstem that’s prone to artifacts. To validate the precision/utility of neuroimaging sequences designed for LC volumetry, we developed a pipeline allowing voxel‐to‐voxel histology to neuroimaging comparisons. We tested this pipeline to analyze the neuro‐histological counterpart of an LC volume obtained from manual segmentation from a MRI neuromelanin(NM)sensitive GRE image.

Method

Whole brain high resolution(0.7mm)3D‐T1 images and 2D‐2mm thick NM‐sensitive axial GRE images of the brainstem were obtained postmortem in situ before brain removal from a single subject using a 7T MRI(Siemens Magnetom). We combined celloidin‐based histological processing and 3D reconstructions of the histology volume at microscopic resolution which was then aligned to T1. We used structures visible in structural MRI(T1)(brainstem surface, red nucleus, and 4th ventricle) to calculate Dice coefficient to measure registration accuracy. Next, we performed an overlap percentage analysis to investigate how well GRE sequence detected LC borders compared to histology.

Result

We ran Dice coefficient analysis for brainstem structures to measure histology to MRI registration accuracy(Table1). The LC GRE to histology masks overlap percentage was 35.29% and 10.77% compared to the MRI and histology mask total voxels(voxel size = 0.34mm3). The overlap percentage obtained for the rostral and middle LC thirds ranged from 9.43% to 75%when compared to total voxels in MRI/histology masks, while the caudal third had zero overlap(Table2,Fig.1).

Conclusion

Our pipeline enables voxel‐to‐voxel correlation analysis between histology and high resolution LC MRIs for neuroimaging validation. The caudal third of the LC in our case has shown a clear lack of overlap potentially due to lack of signal specificity in MRI when compared to the gold standard that is histology. Current analysis of another five other cases is ongoing. Validation of LC MRI signal will inform interpretations of signal results in living patients with the potential to act as a diagnostic tool for ADRD.
Play It Again: Differential pupillometry responses to familiar and unfamiliar music: Findings from typical and atypical Alzheimer’s disease
Authors: Brotherhood Emilie V , Macdougall Amy , Firth Nicholas C. , Pavisic Ivanna M , Mengoudi Kyriaki , Yong Keir X X , Levett Benjamin , Warren Jason D , Camic Paul , Crutch Sebastian J
Published: December 2023

Background

Music has gained more attention than other art forms as a potent tool in supporting cognitive, emotional and social functioning in dementia populations. Methods for measuring moment‐to‐moment responses ‐ rather than comparing pre‐ and post‐stimulus effects ‐ may enable tailoring of musical experiences for the individual. The current study investigated whether differential pupillometry responses could be established for familiar/unfamiliar music in people living with early‐mid stages of typical, memory‐led Alzheimer’s disease (tAD), atypical ‘visual variant’ of Alzheimer’s disease (posterior cortical atrophy; PCA), and healthy age‐matched controls.

Method

Patient groups [tAD = 18; PCA = 21] were recruited via the Specialist Cognitive Disorders clinic at the National Hospital for Neurology and Neurosurgery, London, UK. Healthy older adults [N = 90] were recruited opportunistically via departmental research databases/Join Dementia Research.

Pupillometry responses were recorded while participants listened to 30 musical excerpts [classical (N = 5); 1960s (N = 10), 1970s (N = 10), reversed ‘de novo’ tracks (N = 5)], each rated for familiarity: (a) a priori (known/unknown); (b) self‐rated by participants (not familiar‐extremely familiar); and (c) whether the excerpt evoked a memory (yes/no). Background, basic clinical and music experience information was collected, alongside additional neuropsychological assessment in the patient groups.

Separate linear regression models obtaining cluster robust standard errors were run to predict pupil response from a priori predicted‐ and subjective‐ratings of music familiarity in each participant group, controlling for demographic factors including disease severity.

Result

Results indicate significant within‐group effects of familiarity on pupil response in controls and the tAD group. No effects were observed within the PCA group. Preliminary between‐group analyses including diagnosis as a predictor revealed that, for each music‐pupillometry model, tAD overall pupil dilation responses did not differ significantly compared to controls, however a significant difference was observed between PCA and control pupil dilation responses.

Conclusion

The results are discussed in relation to the preliminary finding of preserved differential pupillometry responses to familiar/unfamiliar music in the tAD group. Although the PCA results question the utility of pupillometry in individuals with significant oculomotor dysfunction, pupillometry may serve as a useful non‐invasive ‘biosignal’ for establishing in‐the‐moment response to music, including in post‐verbal individuals in the later stages of dementia.
Sense of Purpose in Life Predicts Reduced Risk for and Delayed Onset of Mild Cognitive Impairment: A Multistate Survival Model
Authors: Lewis Nathan A , Hofer Scott M , Bennett David A. A , Hill Patrick L
Published: December 2023

Background

With no known cure for Alzheimer’s disease and related dementias, delaying the onset of cognitive decline represents a key target for future dementia research. Sense of purpose has been shown to be associated with high cognitive functioning, more supportive social ties, and greater intellectual activity, and may be valuable for mitigating cognitive impairment both before and following its onset.

Method

Longitudinal data from the Health and Retirement Study (HRS, n = 10,542) and the Rush Memory and Aging Project (MAP, n = 10.48) were used to examine associations between sense of purpose and prospective transitions across normal cognition, mild cognitive impairment (MCI), dementia, and death over up to 12 and 19 years, respectively. Multistate survival modeling examined the impact of sense of purpose on risk for each transition, adjusting for age, sex, education, apolipoprotein‐E allele, and depressive symptoms. Multinomial regression was used to estimate life expectancy in each cognitive state.

Result

More purposeful older adults were found to have lower prospective risk of developing MCI in the HRS (HR = 0.93, 95% CI: 0.90, 0.97) and MAP (HR = 0.82, 95% CI: 0.69, 0.98) and had increased likelihood of improvement in cognitive functioning following MCI classification. In both samples, those higher in sense of purpose were found to have significantly longer overall life expectancy and life expectancy free of cognitive impairment (without MCI or dementia).

Conclusion

Older adults higher in sense of purpose appear to live longer lives, with these differences in life expectancy attributable to increases in years lived without cognitive impairment. Replication of findings across longitudinal studies with disparate samples and measurement procedures provides robust support that having a strong sense of purpose in life contributes to cognitive reserve and resilience. Interventions aiming to promote older adult sense of purpose could extend the cognitive healthspan—the period in which individuals live in a cognitively healthy state free of impairment.