bluuebunny/crossref_metadata_2025 huggingface dataset:
Ratio of serum proBDNF to BDNF and its association with cognitive performance and brain morphometry in mild cognitive impairment
Authors: Cechova Katerina , Angelucci Francesco , Markova Hana , Nikolai Tomas , Matuskova Veronika , Laczó Jan , Nedelska Zuzana , Vyhnalek Martin , Hort Jakub
Published: December 2020

Background

Brain‐derived neurotrophic factor (BDNF) is the neurotrophin well‐known for its role in neurogenesis, synaptic plasticity and enhancement of long‐term potentiation (LTP). Its precursor proBDNF exhibits opposite biological function – inhibits LTP and increases long‐term depression (LTD) in the brain. Altered proBDNF/BDNF ratio in favor of the pro‐form may lead to enhancement of LTD and reduction of LTP in hippocampal neurons with consequent synaptic dysfunction and memory deficits. To explore this hypothesis, we investigated the associations of serum proBDNF, mature BDNF and its ratio (proBDNF/BDNF) with cognitive performance and structural changes of AD‐related brain regions in individuals with amnestic mild cognitive impairment (aMCI).

Method

95 individuals with aMCI (age = 68.5 ± 7.3; MMSE = 26.1 ± 2.4) were recruited from the Czech Brain Aging Study. All participants underwent clinical and laboratory evaluation (with APOE and BDNF genotyping), comprehensive neuropsychological examination and brain MRI (1.5T). FreeSurfer 5.3 software was used to measure left and right hippocampal volume and left and right entorhinal and parahippocampal thickness. Serum levels of proBDNF and BDNF were measured by sandwich enzyme‐linked immunosorbent assay (ELISA).

Result

A negative correlation was found between serum proBDNF/BDNF ratio and verbal memory (r = ‐0. 25, p = 0.04) and executive function (r = ‐0. 30, p = 0.02) but not with other cognitive composite scores (ps > 0.26). A trend of positive correlation was found between serum BDNF levels and verbal memory domain (r = 0.23, p = 0.08). No other correlation between BDNF and proBDNF levels and cognitive performance was significant. Correlations of proBDNF and BDNF levels and its ratio with volume and thickness of AD‐related brain regions were not significant.

Conclusion

Higher proBDNF/BDNF ratio is associated with lower cognitive performance in verbal memory and executive function but not with structural brain changes in aMCI individuals. Our findings suggest that proBDNF/BDNF ratio may be a more reliable blood biomarker of cognitive change than BDNF and proBDNF levels alone.
SNAP25 reflects amyloid‐ and tau‐related synaptic damage: Associations between PET, VBM and cerebrospinal fluid biomarkers of synaptic disfunction in the Alzheimer’s disease spectrum
Authors: Benedet Andréa Lessa , Ashton Nicholas J. , Pascoal Tharick A. , Brinkmalm Ann , Nilsson Johanna , Kvartsberg Hlin , Mathotaarachchi Sulantha , Savard Mélissa , Therriault Joseph , Tissot Cécile , Chamoun Mira , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro
Published: December 2020

Background

It is widely accepted that synaptic dysfunction is an early core feature of Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) biomarkers of synaptic damage have already been associated with amyloid and tau pathologies as well as with cognitive decline in the AD spectrum. However, to the best of our knowledge, no study has yet shown the relationship between CSF biomarkers and PET biomarkers at the voxel‐level for these pathologies. Thus, we aim to investigate the association between several biomarkers of synaptic damage and amyloid and tau, in the AD spectrum, using data from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort.

Method

163 participants (23 young controls, 77 normal controls, 37 mild cognitive impairment, 22 AD and 9 FTD) were evaluated with cross‐sectional CSF biomarkers, [18F]MK6240 and [18F]AZD4694 PET as well as white(WM) and grey matter(GM) MRI voxel‐based morphometry (VBM). For PET, SUVRs were determined using the cerebellar cortex as reference tissue. The CSF biomarkers were quantified by in‐house immunoassays for neurogranin and neuromodulin (GAP‐43), whereas SNAP‐25 and synaptotagmin‐1 (SYT1) were quantified using an immunoprecipitation mass spectrometry method. Linear models were applied to evaluate group differences in CSF biomarker concentrations, adjusting by age and sex. Voxel‐wise linear regressions were also implemented, using VoxelStats, to examine the association between CSF‐ and imaging‐based measures.

Result

Comparison between groups showed increased concentrations of the CSF biomarkers across disease stages (Figure 1). At the voxel level, consistent associations were found between CSF biomarkers and PET amyloid in AD‐related regions, with the SNAP‐25 biomarkers demonstrating the strongest correlations (Figure 2). Regions with clear associations between tau PET and CSF biomarkers were the inferior temporal, frontal and inferior‐parietal cortices. Again, associated regions were common to all biomarkers, with the strongest correlations found with the SNAP‐25 biomarkers (Figure 3). CSF biomarkers also correlated with GM, but not WM, VBM, being the associated areas in regions commonly affected by AD pathophysiology (Figure 4). Further analyses with SV2A PET should corroborate current findings.

Conclusion

These results suggest that CSF SNAP‐25 reflects synaptic degeneration and loss in cortical regions affected by amyloid and tau pathology throughout the continuum.
Higher percent of energy intake as carbohydrates has a negative relationship with cognitive performance in APOE4 carriers
Authors: Sullivan Debra K , Taylor Matthew K , Burns Jeffrey M
Published: December 2020

Background

Expression of the APOE4 allele is a known genetic risk factor of Alzheimer’s Disease. There is speculation that dietary carbohydrate intake may also influence AD risk. The purpose of this study was to evaluate the cross‐sectional relationship between dietary carbohydrate intake and cognitive performance stratified by APOE status in a population of cognitively normal, older adults.

Method

Baseline data from 62 cognitively normal older adults participating in a nutrition intervention study (Nutrition Interventions for Cognitive Enhancement study; NICE study) were analyzed. Dietary intake was obtained by 3‐day diet records and entered into the Nutrition Data System for Research. Fasting blood draws were attained and APOE status was determined by Quest Diagnostics®. A cognitive battery was conducted by a trained psychometrician. Individual test z‐scores were calculated to form domains of memory (Logical Memory Tests I and II and the Free and Cued Selective Recall Test), attention (Digit Span Forward and Backward and Stroop Number Letter), visuospatial processing (Stroop Color, Block Design, Trailmaking A, and Digit Symbol Substitution Test), and executive function (Trailmaking B and Category Fluency Animals/Vegetables). We constructed ordinary least squares regression models to assess the relation between proportion of carbohydrate as energy and cognition controlled for age and gender in an APOE‐dependent manner. Statistical analyses were performed using R (v. 3.6.2; R Foundation, Vienna, Austria). Statistical significance was set at p < 0.05.

Result

Participants were 85% female and had a mean age of 72.1±4.9 years. APOE status was 32% APOE4 carriers (n=20) and 68% non‐carriers. There was no difference in age, sex or dietary macronutrient intake between carriers and non‐carriers. Within APOE4 carriers, higher percent of energy as carbohydrate was related to poorer memory (β̞=‐0.64, p=0.002) and executive function (β̞=‐0.51, p=0.02). Within the non‐carriers, there was no relationship between percent carbohydrate and cognitive performance.

Conclusion

APOE4 carriers with higher percent dietary carbohydrate intake had worse performance on cognitive functions tests. These results support the concept that dietary carbohydrate may be an important modifiable risk factor for AD. These findings will be further investigated utilizing the final sample size of the NICE Study (n=200).
Utility of ioflupane‐SPECT with multimodal imaging in dementia with Lewy bodies
Authors: Miyagawa Toji , Przybelski Scott A. , Maltais Daniela D. , Min Paul H. , Jordan Lennon , Lesnick Timothy G. , Chen Qin , Graff‐Radford Jonathan , Jones David T. , Savica Rodolfo , Knopman David S. , Petersen Ronald C. , Fields Julie A. , Machulda Mary M. , Forsberg Leah K. , Allen Laura A. , Parisi Joseph E. , Murray Melissa E. , Ferman Tanis J. , Dickson Dennis W. , Boeve Bradley F. , Kantarci Kejal , Lowe Val J.
Published: December 2020

Background

Multiple imaging modalities have been individually shown to be useful in diagnosing Dementia with Lewy Bodies (DLB). Reduced striatonigral uptake on ioflupane‐SPECT reflects striatonigral dopamine dysfunction observed in DLB, while other imaging modalities assess different aspects of DLB, which potentially work complementarily when used together. We assessed how well ioflupane‐SPECT differentiates DLB from Alzheimer’s Disease Dementia (ADem) and whether adding another imaging modality to ioflupane‐SPECT would provide additional value.

Method

Ioflupane‐SPECT, MRI, FDG‐PET, and PiB‐PET were assessed on 35 DLB and 14 ADem patients (including 12 patients with eventual autopsy confirmation). Striatonigral dopamine transporter uptake was evaluated semi‐quantitatively with ioflupane‐SPECT using DaTQUANT software (GE Healthcare) to calculate z‐scores of putamen uptake. Hippocampal volume was calculated with structural MRI, cingulate island sign (CIS) ratio with FDG‐PET, and global cortical PiB retention with PiB‐PET.

Result

Lower DaTQUANT z‐scores of putamen were observed in DLB patients compared to ADem patients (c‐statistic 0.896, p<0.001). Ioflupane‐SPECT showed higher c‐statistic in differentiating DLB from ADem than hippocampal volume on MRI (c‐statistic 0.718, p=0.034), CIS on FDG‐PET (c‐statistic 0.869, p=0.003), or global cortical PiB retention on PiB‐PET (c‐statistic 0.869, p=0.002), but some overlap between two diagnostic groups was still observed with the single imaging modality. Among these imaging modalities, ioflupane‐SPECT was the only modality correlated with the Unified Parkinson Disease Rating Scale (UPDRS) part III, while only PiB‐PET correlated with Montreal Cognitive Assessment (MoCA) test score. Adding another imaging modality to ioflupane‐SPECT enhanced c‐statistics (+MRI c‐statistic 0.931, p<0.001; +FDG‐PET c‐statistic 0.957, p=0.005; +PiB‐PET c‐statistic 0.955, p=0.007), and ioflupane‐SPECT in combination with both FDG‐PET and PiB‐PET showed the highest c‐statistic of 0.974 (p=0.043).

Conclusion

Ioflupane‐SPECT is an excellent imaging modality to identify DLB by detecting striatonigral dopamine dysfunction which is strongly associated with motor impairment in DLB. Correlative neuroimaging with MRI, FDG‐PET, or PiB‐PET may add small incremental value in differentiation of DLB and ADem. Supported by NIH grants (AG016574, AG006786, AG015866, NS100620, AG062677), grant from GE Healthcare, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, the Deal Family Foundation, and the Little Family Foundation.
But will they use it? Factors influencing sustained use of a digital memory notebook application by individuals with mild cognitive impairment
Authors: Schmitter‐Edgecombe Maureen , Brown Katelyn , Faust Emily , Holder Larry , Cook Diane , Cunningham Reanne , Sumida Catherine
Published: December 2020

Background

Advances in technology have fueled new opportunities to improve external compensatory devices. The Digital Memory Notebook (DMN) is an iOS tablet application (app) developed in collaboration with older individuals with mild cognitive impairment (MCI) to support functional independence. To understand users for whom DMN training was beneficial, we examined data from a pilot clinical trial for factors that influenced sustained use of this compensatory tool.

Method

Twenty‐five participants (M age = 72; M education = 16; 48% female) with MCI learned to use the DMN app in 5‐6 (two‐hour) training sessions delivered within one‐month. Participant use of the DMN app was then monitored through real‐time collection of data usage metrics for an additional three months. Based on app use during the third‐month post‐training, participants were divided into DMN user (N = 13; M daily distinct uses = 4.5) and non‐user (N = 12) groups. Demographics, clinician ratings, baseline clinical measures and DMN usage metrics were all examined.

Result

No group differences emerged in demographics, pre‐morbid ability estimate (High Average), or clinician ratings of motivation, comprehension, insight and competency during training sessions. DMN non‐users exhibited lower scores on standardized measures of global cognitive status (Low Average vs. Average) and memory (Borderline vs. Low Average), and self‐reported poorer everyday memory. DMN usage metrics captured during training revealed no group differences in week one (sessions 1‐2). By week two (session 3), DMN non‐users showed fewer daily distinct uses of the DMN (4 vs. 8). During weeks 3 and 4, DMN non‐users continued to show fewer daily distinct uses as well as fewer interactions with all sections of the app (i.e., calendar, daily event scheduling, notes and journal). Non‐users also demonstrated poorer use of advanced app functions during training (e.g., high priority scheduling, reminder alarms, picture use, prospective memory use).

Conclusion

Individuals with MCI who were actively using the DMN three‐months post‐intervention were less cognitively impaired, demonstrated greater DMN use as early as week two of training, and made use of advanced functions. Next steps include increasing DMN use through early adaptive learning and continued automated booster training.
Development of a clinical practice model of music therapy to address psychosocial functioning for persons with dementia
Authors: Reschke‐Hernandez Alaine E
Published: December 2020

Background

Emerging research and anecdotal evidence suggest that music therapy and related music interventions may effectively target affective, psychosocial, and behavioral goals for individuals with dementia. However, such research has been criticized for its lack of methodological rigor as well as insufficient detail regarding theoretical foundation of the intervention, characteristics of the music itself, interventionist training, and protocol adherence.

Method

The purpose of this research was to develop a Clinical Practice Model of music therapy for individuals with dementia. The model was developed in four phases. In the first phase, I applied the Therapeutic Function of Music Worksheet (Hanson‐Abromeit, 2005) to current practice with dementia patients to foster understanding of how music itself contributes to the efficacy of therapeutic music interventions. I used text analysis software to facilitate interpretation of the completed worksheet. Next, I performed an exhaustive literature review of music and non‐music strategies for working with this population, 1970‐2017. I collected anecdotal strategy suggestions from dementia care specialists. I then informally piloted each strategy in my clinical practice. The results of the first two steps yielded thematic categories of strategies grounded in research evidence and clinical wisdom. In step three, a panel of dementia care experts validated these themes and associated strategies. This process ensured all aspects of evidence‐based practice were present in the model. Finally, I tested a music therapy intervention, grounded in the model, through a randomized clinical crossover trial.

Result

The model that emerged from this research is theoretically grounded in the biopsychosocial model of healthcare and Kitwood’s personhood framework. It includes an organizational schema for applying intervention strategies within six thematic areas: cognition, attention, familiarity, audibility, structure, and autonomy.

Conclusion

The Clinical Practice Model offers a foundation for holistically considering individual’s needs and strengths and guidance for systematic intervention design and research. It predicts that an intervention built upon this schema will influence social‐affective responses, wellbeing, and in turn, psychosocial symptoms of dementia. While the model is likely to evolve as new knowledge is gained, it has great implications for research, clinical practice, and education in music therapy and related healthcare professions.
Prevalence and participant characteristics associated with subjective memory complaint: Results from the Maule Cohort
Authors: Oyarzun‐Gonzalez Ximena , Toro Pablo , Abner Erin L , Ferreccio Catterina
Published: December 2020

Background

Subjective memory complaints (SMC) are common in later life and have been associated with increased risk of cognitive impairment and dementia. While there is much interest in SMC globally, no population‐based studies from South America have reported SMC prevalence.

Method

Data for this analysis was drawn from the Maule Cohort (MAUCO), a population‐based prospective cohort of Molina, Chile residents aged 35‐74 at baseline. MAUCO participants were stratified at age 60. Presence of SMC was determined by the questions “Does your memory fail frequently? Or Do you forget events, even recent, or some appointments?” Prevalence of SMC was estimated within age groups. Logistic regression was performed within age groups to evaluate factors associated with SMC.

Results

Most participants were female (56%), married (66%), with ≤ 8 years of education (49%), and reported good health (39%). There were 6,203 participants aged < 60, and 2,517 aged ≥ 60. Prevalence of SMC was 16% and 24%, respectively. Within age groups, characteristics of participants who reported SMC were different. Among those age < 60, those who reported SMC were more likely to use antidepressants, but this was not the case among the older group. In both age groups, those who reported SMC had significantly higher polypharmacy, higher anticholinergic burden, and higher use of benzodiazepines. Logistic regression analysis showed that for the age < 60 group, being female, having bad self‐reported health (OR=2.4; 95% CI 1.4‐4.3), depression (OR=1.5; 1.1‐1.9), major depressive syndrome on PHQ‐9 (OR=3.0; 2.2‐4.1) and MMSE score (OR=0.97; 0.94‐0.99) were significantly associated with SMC. However, in the older group, only the history of cancer (OR=2.0; 1.1‐3.8), major depressive syndrome on PHQ‐9 (OR=2.7; 1.6‐4.7), depressive symptoms on PHQ‐9 (OR 1.50; 1.03‐2.15), and MMSE score (OR=0.92; 0.89‐0.94) were associated with odds of SMC. In the adjusted models, neither polypharmacy, use of benzodiazepines, nor high anticholinergic burden were significant in any of the models for the younger or older groups.

Conclusion

SMC was common in both younger and older MAUCO participants. SMC may be associated with different factors in younger vs. older adults, but was associated with objective cognitive function (MMSE) in both groups.
Leveraging predicted gene expression data for recapitulation of gene coexpression network analysis associations with AD pathology and cognitive decline
Authors: Seto Mabel , Janve Vaibhav A. , Logsdon Benjamin A. , Mostafavi Sara , Dumitrescu Logan , Mahoney Emily R. , Gaiteri Chris , Schneider Julie A. , Bennett David A. , De Jager Philip L. , Hohman Timothy J.
Published: December 2020

Background

Gene co‐expression network (GCN) analysis is an approach in which biologically relevant modules can be identified from gene expression data, allowing for the elucidation of biological functions that are associated with Alzheimer’s disease (AD). Here, we evaluate the associations between generated from dorsolateral prefrontal cortex RNA sequencing (RNAseq) to validate previous reports (Mostafavi et al., 2018) and to identify novel module‐trait associations. As RNAseq data is often limited, we also apply an emerging technique to generate the same modules to provide a proof‐of‐concept for how transcriptomic reference panels can be leveraged to apply GCNs in the context of genome‐wide association analyses.

Method

Genotype, neuropsychological data, autopsy measures of AD pathology, and RNAseq were obtained from the Religious Orders Study and Rush Memory and Aging Project. Global cognitive composite scores were calculated from 17 neuropsychological tests. Predicted gene expression data were generated using . Using 66 reported AD co‐expression modules (Logsdon et al. 2019; Mostafavi et al. 2018), we performed linear regression analyses assessing the association between the first principle component of the and cognitive decline and AD neuropathology. Covariates included age of death, sex, education, and post‐mortem interval. Correction for multiple comparisons was completed using the false discovery rate procedure.

Result

We recapitulated all reported associations. We also identified 15 novel associations with AD phenotypes using module definitions reported by Logsdon et al. Using predicted gene expression data, we replicated grey60 associations with tangles (p = 0.009) and cognitive decline (p = 0.004). The hub gene of grey60 was PAPOLA, which is a nominated target from AMP‐AD. PrediXcan analyses also recapitulated the m111 association with cognitive decline (p = 0.03, hub gene = TCF12). Both modules were enriched for transcriptional regulation genes, and higher gene expression in both modules was associated with slower cognitive decline.

Conclusion

Predicted gene expression can serve as a surrogate for recapitulating aspects of GCN analyses when RNAseq data is limited. Our findings provide additional evidence that gene networks involved in transcriptional regulation contribute to the neuropathology and cognitive decline observed in AD.
The evolution of brain atrophy across the disease spectrum of familial frontotemporal dementia
Authors: Staffaroni Adam M. , Goh Sheng‐Yang Matthew , Cobigo Yann , Ong Elise , Lee Suzee E. , Casaletto Kaitlin B. , Wolf Amy , Forsberg Leah K. , Ghoshal Nupur , Graff‐Radford Neill R. , Grossman Murray , Heuer Hilary W. , Hsiung Ging‐Yuek Robin , Kantarci Kejal , Knopman David S. , Kremers Walter K. , Mackenzie Ian R. , Miller Bruce L. , Pedraza Otto , Rascovsky Katya , Tartaglia Carmela , Wszolek Zbigniew , Kramer Joel H. , Kornak John , Boeve Bradley F. , Boxer Adam L. , Rosen Howard J.
Published: December 2020

Background

Familial frontotemporal dementia (f‐FTLD) is typically caused by mutations in one of three genes: microtubule‐associated protein tau (MAPT), progranulin (GRN), and a repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene. Accurate characterization of the natural history of each mutation is important for clinical prognostication and clinical trial design, and it could shed light on disease biology. Such models have not been thoroughly developed using participants that represent all disease stages, with longitudinal data. We characterized the trajectory of atrophy in each gene by using longitudinal voxel‐wise analyses of gray matter volume, and we assessed whether functional independence declined in tandem.

Method

F‐FTLD participants (n=100) with a known mutation (MAPT+ (n=28), GRN+ (n=33), C9orf72+ (n=39)) were grouped according to disease stage (CDR®+NACC FTLD module). We included participants with at least two structural MRIs at a given disease stage: presymptomatic (CDR®+NACC‐FTLD=0, n=57), mild/questionable (CDR®+NACC‐FTLD=0.5, n=15), and symptomatic (CDR®+NACC‐FTLD ≥1, n=28). We fitted longitudinal linear mixed effects models to extract mean atrophy rates in each lobe compared to longitudinal imaging from family members without mutations (n=60). All results presented below were significant at p<.001.

Result

Using the left frontal lobe as an exemplar, in the presymptomatic stage, MAPT mutation carriers showed the greatest rate of atrophy compared to controls (88 mm3/year more volume loss than controls), followed by GRN+ (65 mm3/year) and then C9orf72+ (49 mm3/year). In the mild/questionable stage, MAPT+ showed a greater divergence from controls (374 mm3/year) than did GRN+ (107 mm3/year) or C9orf72+ (223 mm3/year). In the symptomatic stage, MAPT+ again lost volume at the fastest rate (2,099 mm3/year), followed by GRN+ (1,360 mm3/year). C9orf72 expansion carriers showed a much slower rate of volume loss (115 mm3/year). Similar patterns were observed for other brain regions. In contrast to the imaging results, C9orf72+ exhibited similar rates of functional decline compared to GRN+ and MAPT+ at all levels of disease severity.

Conclusion

The primary f‐FTLD genes show divergent atrophy trajectories as a function of disease stage, with C9orf72 expansion carriers exhibiting a slow degeneration throughout the disease course, possibly due to unique pathophysiological mechanisms.
Exploring genetic contributors to neuroprotection from AD pathologies: A genome‐wide association study
Authors: Seto Mabel , Mahoney Emily R. , Dumitrescu Logan , Engelman Corinne D. , Deming Yuetiva , Albert Marilyn S. , Johnson Sterling C. , Zetterberg Henrik , Blennow Kaj , Jefferson Angela L. , Hohman Timothy J.
Published: December 2020

Background

Preclinical Alzheimer’s disease (AD) is a term describing individuals who harbor neuropathological hallmarks of AD but are asymptomatic. We hypothesize that common genetic variation contributes to neuroprotection from AD pathology. More specifically, we tested whether genetic variation modifies the association between AD pathology (measured by CSF biomarkers) and neurodegeneration (measured by hippocampal volume).

Method

MRI measurements of hippocampal volume and CSF measures of amyloid (Aβ42) and tau were obtained from 1,073 individuals of European descent from four longitudinal aging cohort studies (age = 70.7 ± 8.7; female = 47%; normal cognition = 38%). Data were harmonized leveraging established procedures to account for differences in site, data acquisition, and processing. A genome‐wide association study was performed using mixed‐effects regression models to assess SNP x CSF biomarker interactions on hippocampal atrophy. Covariates included age, sex, population principal components, cohort, and time.

Result

We identified a locus that modifies the association between baseline CSF Aβ42 and hippocampal atrophy in an intronic region of the SEMA5B gene (index SNP = rs62263260; p = 1.97e‐8; MAF = 0.12; Figure 1). Carriers of the rs62263260 minor allele showed a faster rate of hippocampal atrophy, particularly among those harboring high levels of amyloid pathology. This variant is also an eQTL for SEMA5B in brain tissue (GTEx p = 4.80e‐4), where minor allele carriers express higher levels of SEMA5B, suggesting that lower SEMA5B expression may provide neuroprotection. Additionally, we identified a locus that modifies the association between baseline CSF p‐tau and hippocampal atrophy on chromosome 3 proximal to the SATB1 gene (index SNP = rs116216974; p = 1.62e‐8, MAF = 0.02%). Carriers of the rs116216974 minor allele had a slower rate of hippocampal atrophy in the presence of high baseline p‐tau pathology compared to non‐carriers. No eQTLs were reported for rs116216974.

Conclusion

We identified two independent genetic loci that modify the association between AD biomarkers and neurodegeneration. SEMA5B is implicated in synapse elimination, and increased elimination may occur in the presence of amyloid pathology. SATB1 knockdown in mice is associated with increased microglial activity, suggesting that regulating the immune response to p‐tau may be important for neuroprotection. This study also demonstrates that identifying genetic factors contributing to neuroprotection from AD pathology may help elucidate mechanisms behind asymptomatic AD.
Engagement in social activities is related to connected speech and language outcomes in the Wisconsin Registry for Alzheimer's Prevention
Authors: Mueller Kimberly D. , Peters Cassandra C. , Hulle Carol A. , Koscik Rebecca L. , Jonaitis Erin M. , Betthauser Tobey J. , Chin Nathaniel A. , Hermann Bruce P. , Johnson Sterling C.
Published: December 2020

Background

There is growing interest in using digital biomarkers, like recorded spontaneous speech, as indicators of Alzheimer’s disease progression. Several studies have shown that changes in connected speech and language (CSL), including speech fluency markers and linguistic content, are associated with preclinical cognitive decline. Little is known about the relationships between CSL and the lifestyle factors that may be largely dependent upon it, particularly social participation. Social engagement (SE) (e.g., in activities such as informal social participation, volunteering) has been associated with multiple health indicators in aging. Our aim was to determine if SE at baseline, or change in SE, was related to declines in CSL measures that have been linked to cognitive decline. Sensitivity analyses determined if baseline CSL predicted baseline SE and change in SE.

Method

Longitudinal CSL measures (Figure 1) were automatically extracted from picture description transcripts from Wisconsin Registry for Alzheimer’s Prevention participants (N=794). SE composite scores were created from selected Florida Cognitive Activities Scale items (Table 1). Statistics included t‐tests, chi‐square tests, ANCOVA, and linear mixed‐effects models with CSL as outcomes and baseline SE, and normalized change from baseline to most recent SE, as predictors.

Result

Table 2 shows speech metrics and demographics of participants stratified by low, medium and high SE. Participants reporting “high” SE were more likely to be female, had higher baseline WRAT‐3 reading scores, and had lower depression scores. Participants reporting “low” SE expressed fewer content words, unique words, and total words than those with mid‐ or high SE. Positive change in SE was associated with slower age‐related change in speech fluency over time (Table 3, Figure 2). Sensitivity analyses indicated worse baseline speech fluency was significantly associated with higher baseline SE but also positive change in SE, adjusting for age, sex WRAT‐3 and depression (Table 4).

Conclusion

This study shows that spontaneous speech metrics are positively associated with self‐reported social engagement in late middle age. Crucial next steps include determining if SE moderates the effect of amyloid, tau, and neurodegeneration on measures of cognition including speech. SE is a potentially modifiable lifestyle behavior that may have positive implications for improved outcomes in communication and cognitive function.
Lifetime stressful experiences and cognitive performance in African American and white older adults: New evidence from a population‐based cohort
Authors: Zuelsdorff Megan , Sonnega Amanda , Byrd DeAnnah R , Benton Susan Flowers , Turner Robert
Published: December 2020

Background

Growing evidence suggests that modifiable sociocontextual factors powerfully shape health including risk for Alzheimer's disease and related dementias (ADRD), and contribute substantially to well‐established racial disparities in cognitive aging. Stressful experiences cluster and accumulate across the lifespan, plausibly impacting brain health, but cognitive effects of lifetime adversity across diverse populations remain underexplored. We examined relationships between lifetime stressful events and cognition among African American and White older adults in the Health and Retirement Study (HRS).

Method

The study sample included non‐demented adults (N=8,222) aged 60 and older who provided cognitive and lifetime stress data at the 2006/08 and 2010/12 HRS waves. Cognitive outcomes included performance on a test of global cognition (Telephone Interview for Cognitive Status) and its immediate and delayed recall subscales. The key predictor of interest was a Lifetime Stress index score (sample range=0‐11 experiences). Mixed‐effects regression models assessed associations of lifetime stress with each cognitive outcome. Polynomial and three‐way interaction models explored potential (1) non‐linear associations between stress and cognition, and (2) moderation of those relationships by race.

Result

African Americans (N=1,015) were younger (M=71.7, SD=6.8) than whites (M=72.2, SD=6.3) and reported fewer years of education (p<0.001). Reported number of stressful life events reported (M=1.61, SD=1.45) did not vary by race. In adjusted models (Table 1, Model 2), a significant stress quadratic revealed that relationships with global cognition (p<0.001) and delayed recall (p=0.01) were non‐linear. Modification by African American race (Table 1, Model 3; Figure 1) was observed for global cognition (p=0.01) but not recall subscales (immediate: p=0.10; delayed: p=0.45).

Conclusion

We found that lifetime stress is associated with poorer later‐life cognitive function; however, detriment is observed only at high levels of stress. African American and White HRS participants report very few stressful life events on average, but African Americans reporting many stressors showed exacerbated stressor‐associated dysfunction in global cognition. Our findings from this large, population‐based sample reaffirm the role for stress and stress‐adjacent experiences in cognitive aging, particularly among communities facing disproportionate ADRD burden. Expanding community‐specific, lifecourse‐based research and intervention strategies is a necessary next step toward understanding and mitigating disparity through targeted resource placement and stakeholder partnerships.
In a pre‐pivotal diagnostic study, β‐amyloid plaque detection in the lens of the eye in MCI and mild AD patients was used to classify subjects as normal, MCI, and mild AD using Sapphire II
Authors: Knowlton Newman , Hendrix Suzanne B. , Wilke Susanne , Nilan Dennis
Published: December 2020

Background

The Sapphire II platform is a clinical diagnostic device intended for aiding clinical evaluation and measurement of beta‐amyloid aggregation in anatomically defined regions of the anterior segment of the eye. It detects a specific fluorescent signature emission of ligand‐marked beta amyloid complex in the supranuclear region of the human lens. The current study results are Sapphire II scan to be used to classify patients as normal, MCI and mild Alzheimer’s disease and the utility of Sapphire II screening compared to b‐amyloid PET scans in MCI and Mild AD subjects.

Method

A naïve Bayes classifier using a base model with the three most theoretically relevant parameters (τ1, τ2, φ). Sensitivity and specificity is assessed comparing the normal group to the collective MCI/Mild AD group. 48 participants; 28 MCI, 16 Mild AD patients and 4 Normal Control subjects were studied.

Results

The Sapphire II naïve Bayes classifier with cross validation had sensitivity of 96%, specificity of 75%, and overall accuracy of 92%. Results based on 4 healthy controls only, with one of the control subjects tested positive in Sapphire II; additional testing on 10 healthy controls is in progress

Conclusion

Sapphire II offers a non‐invasive, safe, easy to use, community based inexpensive method for accurately classifying individuals as normal, MCI or mild AD dementia on the basis of the beta amyloid in the lens of the eye. Sapphire II may offer a practical alternative to PET amyloid scans for biomarker confirmed AD diagnosis. Evaluation of individual PET scans and cognitive testing suggests that Sapphire II is more sensitive than PET. ^Discussions with Dr. Tae Yeon Yoo, Ph.D. are gratefully acknowledged.
Detecting biological changes in longitudinal MRI scans of Alzheimer’s disease patients in the hippocampus region with deep learning
Authors: Dong Mengjin , Xie Long , Das Sandhitsu R. , Wolk David A. , Yushkevich Paul A.
Published: December 2020

Background

Alzheimer's Disease (AD) is characterized by gradual loss of gray matter, particularly in the medial temporal lobe (MTL) and hippocampus. Longitudinal change in hippocampal volume on MRI is an effective biomarker to monitor disease progression in AD. However, neurodegenerative changes in the hippocampus on longitudinal MRI can be obscured by differences in MRI signal that are unrelated to disease progression, such as different amounts of head motion, noise, or MRI artifact. We hypothesize that a deep learning model can be trained to distinguish true biological changes from nonsystematic factors, leading to a more sensitive biomarker of disease progression.

Method

A 3D convolutional neural network (CNN) was trained to predict the inter‐scan interval (in days) from pairs of rigidly co‐registered longitudinal T1‐weighted MRI scans. Scans trimmed to the hippocampus region were input in arbitrary time order, and the network had to infer which was the earlier scan and the interscan interval in days. A cohort of 666 ADNI participants was used for CNN training and 154 participants formed a held‐out test set. We tested the hypotheses that (a) CNN can correctly predict the temporal order of scans (indicating sensitivity to biological changes) and (b) that a measure of mismatch between actual interscan interval and interval predicted by a CNN trained on more impaired subjects (late MCI and AD) would differ between less impaired (controls + early MCI) and more impaired groups (indicating sensitivity to AD). The same hypotheses were also tested using a conventional technique for longitudinal change estimation, ALOHA (Das et al., 2012).

Result

CNN was more accurate than ALOHA in inferring the temporal order of scans (Table 2, Figure 1) and to a lesser extent, inter‐scan interval (Table 3, Figure 2). Mismatch measure was greater for the less impaired than more impaired group for both CNN and ALOHA, with larger difference for CNN, potentially indicating greater sensitivity to disease.

Conclusion

CNN can accurately detect the temporal order of scans indicating sensitivity to neurodegeneration and ability to factor out non‐systematic changes. The CNN‐derived mismatch measure has the potential to serve as a disease progression biomarker for AD clinical trials.
Lower cerebral oxygen utilization is associated with Alzheimer’s disease‐related neurodegeneration on MRI and poorer cognitive performances among apolipoprotein E ε4 carriers
Authors: Robb W. Hudson , Khan Omair A. , Ahmed Humza A. , Liu Dandan , Moore Elizabeth E. , Li Judy , Cambronero Francis E. , Pechman Kimberly R. , Gifford Katherine A. , Landman Bennett A. , Hohman Timothy J. , Jefferson Angela L.
Published: December 2020

Background

Oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2) are markers of oxygen utilization and neuronal energy demands that may offer insights into normal and abnormal changes in aging. This study cross‐sectionally related OEF and CMRO2 to cognitive and structural neuroimaging variables among older adults. Because apolipoprotein E (APOE)‐ε4 status is an Alzheimer’s disease (AD) genetic risk factor and a molecular mediator of vascular damage, we tested whether APOE‐ε4 status modified associations.

Method

Vanderbilt Memory and Aging Project participants free of stroke and dementia (n=237, 75±7 years, 37% female) underwent neuropsychological testing and multimodal 3T brain MRI, including T
1‐weighted imaging (grey matter volumes/thickness), fluid attenuated inversion recovery (white matter hyperintensities (WMHs)), T2‐relaxation‐under‐spin‐tagging (venous oxygenation (Yv)), and pseudo‐continuous arterial spin‐labeling (cerebral blow flow (CBF)). Participant‐specific Yv, arterial oxygenation, and hematocrit were used to calculate OEF, which multiplied by CBF yielded CMRO2. Linear regressions related OEF and CMRO2 individually to cognition, grey matter volumes, an AD imaging signature (Schwarz et al., 2016), and WMHs adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, Clinical Dementia Rating, APOE‐ε4 status, and (as appropriate) intracranial volume. Follow‐up models tested predictor x APOE‐ε4 status interactions on outcomes followed by APOE‐ε4 status stratification.

Result

Main effects were mostly null (p‐values>0.04). APOE‐ε4 status interacted with both OEF and CMRO2 on language (p‐values<0.04), episodic memory (p<0.04), hippocampal volume (p‐values<0.03), and Schwarz AD signature (p‐values<0.05). APOE‐ε4 status also interacted with CMRO2 on total grey matter volume (p=0.04), inferior lateral ventricle volume (p=0.01), executive function (p=0.05), and visuospatial skills (p=0.01). For all interactions, lower OEF and CMRO2 related to worse cognitive performances and smaller regional grey matter structures in APOE‐ε4 carriers only.

Conclusion

APOE‐ε4 status modifies associations linking cerebral oxygen metabolism markers (CMRO2, OEF) to worse episodic memory performance and smaller neuroimaging variables in regions susceptible to AD‐related neurodegeneration. Consistently, results are present in APOE‐ε4 carriers only. Congruence between cognitive and neuroimaging findings suggests that oxygen metabolism and APOE‐ε4 may interact early in the pathogenesis of AD and related neurodegeneration with important clinical consequences.
Characterization of genetic expression patterns in MCI using a multiomics approach and neuroimaging endophenotypes
Authors: Sanjay Apoorva Bharthur , Patania Alice , Yan Xiaoran , Svaldi Diana , Apostolova Liana G.
Published: December 2020

Background

Our goal was to characterize gene expression patterns at the MCI stage using a multiomics approach involving the integration of neuroimaging MRI data and peripheral blood‐based gene expression data.

Method

Data from the ImaGene study (Imaging and Genetics Biomarkers study of Alzheimer’s Disease, UCLA) was used. This included 160 subjects clinically diagnosed with amnestic MCI (n=70), non‐amnestic MCI (n=38) and normal controls (n=52)(Table 1). Coronal T1‐weighted MPRAGE scans were processed in Freesurfer 6.0 using the standard processing pipeline and atrophy measures were obtained. Quantile‐normalized and log‐transformed mRNA levels were obtained from peripheral blood. Preliminary data reduction was performed by selecting 3420 genes whose expression was significantly associated with hippocampal volume and cortical thickness (p<0.05, linear regression model). Vertex‐wise regressions were performed in SurfStat to map the associations of peripheral blood‐based gene expression with brain atrophy. A persistent‐homology pipeline was applied on the regression‐derived beta‐coefficients to derive betti numbers characterizing the association between gene expression and brain topology (Figure 1). The betti numbers were then used in a kernel‐based clustering solution to cluster genes. PCA was used to represent each cluster by its first principal component. Clusters of genes significantly associated with disease diagnosis were identified. Significant clusters were characterized ontologically to identify enriched biological pathways within the clusters. Cluster level association of genes with brain regions was then assessed using vertex wise regressions in SurfStat (Figure 3).

Result

The 3420 genes clustered into 20 clusters with good separation (Figure 2). Three disease‐relevant significant clusters emerged (pFDR‐Corrected<0.05) and were validated using a null model. The biological processes associated with each cluster were mitochondrial fatty acid beta oxidation, as well as regulation of NF‐kappaB signaling and apoptosis (Figure 2). Cluster‐level associations with cortical thickness displayed canonical AD‐like patterns (Figure 3).The apoptosis cluster showed a very strong AD like presentation with respect to atrophy pattern.

Conclusion

Using a data‐driven approach, we found a systems‐level disease‐relevant gene expression signature that is sensitive to pre‐clinical AD using peripheral blood showing an AD‐like pattern of association with cortical atrophy. This approach might be useful in developing robust risk assessment platforms.
Interactive effects of chronic health conditions and financial hardship on episodic memory among older blacks: Findings from the Health and Retirement Study
Authors: Byrd DeAnnah R , Gonzales Ernest , Moody Danielle L Beatty , Marshall Gillian L , Zahodne Laura B , Thorpe Roland J , Whitfield Keith E
Published: December 2020

Background

Previous research suggests that chronic health conditions and financial hardship robustly shape cognitive health outcomes, including ADRD risk in older Blacks. However, few studies have explored the moderating effect of financial hardship on chronic disease burden and specific cognitive domains. This study examined whether financial hardship modifies the impact of self‐reported chronic health conditions on episodic memory among a representative sample of older Blacks enrolled in the 2006 Health and Retirement Study (HRS).

Method

The study included 934 older Blacks (50+ years) who completed the psychosocial leave‐behind questionnaire in the 2006 wave of the HRS. Episodic memory included a composite standardized score of immediate and delayed recall. Six chronic health conditions (e.g., hypertension, diabetes, stroke) were summed and dichotomized (0‐1 vs. as ≥2 conditions). Financial hardship was assessed as self‐reported difficulty paying monthly bills (range: not at all=0 to very/completely=3). Weighted OLS regression models tested independent associations between chronic health conditions and episodic memory, controlling for sociodemographic characteristics. An interaction term tested moderation by financial hardship.

Result

The majority of the sample was female (39.34% male) and had less than a high school education (35.89%; Table 1). Financial hardship modified the association between chronic disease burden and episodic memory performance such that individuals who reported very little difficulty paying their monthly bills had significantly lower memory scores at high levels of disease burden compared to those reporting high financial difficulty after controlling for age, gender, education and income (F 2, 49 = 4.97, p= 0.011; see Table 2 and Figure 1).

Conclusion

The present study adds to our understanding of cognitive aging among older Black Americans. Results support previous research, pointing to the independent negative effects of both chronic diseases and subjective financial burden, but also extend the literature by suggesting an interactive effect. Specifically, multimorbidity was more strongly associated with worse episodic memory functioning among older Blacks with less financial hardship, which appeared to be driven by the relatively low cognitive functioning among those with the greatest financial hardship. This pattern of results suggest that financial hardship may be just as consequential for cognitive aging as chronic diseases for older Blacks.