bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of Research Community Characteristics in Engagement and Recruitment to Dementia Research
Authors: Bergey Abigail E , Gabela Nicole Taikeff , Jackson Jonathan D. , DeSousa Elma , Reynolds Marissa L. , Bennett Erin E
Published: December 2023

Background

Research studies and clinical trials in Alzheimer’s disease and related dementias (ADRD) attract only socio‐demographically advantaged populations, despite a higher risk of ADRD in historically marginalized and minoritized populations (HMM). Advancements in participant recruitment, retention, and engagement (RER), and clinical research design are urgently needed to address ADRD disparities and inequities. In light of these critical shortfalls in diverse and representative RER, this mixed‐methods study assesses RER strategies as well as the context in which these strategies are practiced within the ADRD Centers Program.

Methods

Semi‐structured interviews and focus groups were conducted across four ADRD research centers and their respective surrounding communities. Interviews were conducted with research and non‐research faculty, research staff, faith and civic leaders, patients, care providers, and community members. Geospatial mapping tools were used to better define where current RER practices were being focused relative to where HMM and high‐risk populations resided.

Results

Extracted themes demonstrated that current diversity, equity, and inclusion efforts (DEI) from sites inefficiently connected HMM communities with ADRD research institutions. Instability in collaborative culture and a lack of grounded, fully embraced DEI efforts were cited in driving the divide between HMM and research communities. Inequitable burden of funding and sustaining DEI efforts, as well as the diffused impact in HMM communities further limited RER activities targeting HMM and high‐risk populations. Geospatial analysis additionally revealed that RER activities tended to occur proximal to advantaged populations, rather than in spaces accessible to HMM and high‐risk communities.

Conclusion

The current study sought to assess RER strategies as well as the context in which these strategies are practiced to better understand motivations and barriers within NIA’s ADRD Centers Program. This sharper degree of information and clarity regarding RER activities may yield precision RER strategies and resources.
Genetic context controls microglia‐induced neuronal damage in Alzheimer’s disease
Authors: Heuer Sarah E , Keezer Kelly J , Hewes Amanda , Onos Kristen D , Bloss Erik B , Howell Gareth R
Published: December 2023

Background

The activation of microglia and the loss of synapses have emerged as key events in Alzheimer’s disease (AD) progression, yet the relationship between these processes is not clear. Previous studies suggest genetic variation controls microglial activation in AD mouse models, so we evaluated how the elimination of brain microglia influenced synapses on hippocampal pyramidal cells across two genetically distinct AD mouse models.

Method

Using a viral approach, we labeled hippocampal neurons that project to the frontal cortex by expressing GFP in young (3m) inbred C57BL/6J and genetically distinct PWK/PhJ female mice with or without a transgenic (APP/PS1) allele that drives amyloid pathology. At 4m we placed half of the mice on diet formulated with CSF1R inhibitor PLX5622 to deplete brain microglia. At 8m, a time when plaque pathology is present in transgenic mice, we examined cognition using the delayed spatial task. We then analyzed the density and morphology of spines across multiple dendritic domains, as well as amyloid plaques and markers of disease‐associated (DAM) and interferon responding (IRM) states of IBA1+ microglia.

Result

While spatial cognition was unaffected by PLX5622, we identified B6.APP/PS1 as susceptible and PWK.APP/PS1 as resilient to cognitive deficits at 8m. Across both strains, PLX5622 depleted hippocampal microglia but did not affect amyloid plaques. In contrast, we observed strain differences in spine synapse density and morphology. Compared to spine stability across PWK wild‐type (WT) and APP/PS1 mice, we measured increased density of small spines in B6.APP/PS1 mice (compared to WT). B6.APP/PS1 mice showed reduced spine density with PLX5622, whereas PWK.APP/PS1 mice remained unaltered. These changes in spine density corresponded to DAM being resistant to depletion with PLX5622 in APP/PS1 mice (especially B6), whereas IRM were susceptible, suggesting a neuroprotective role for IRM.

Conclusion

We show here that genetic context determines how synapses on CA1 projection neurons respond to the depletion of brain microglia and AD transgenes. Since PWK.APP/PS1 are resistant to hippocampal neuronal damage with robust microglia activation, this strain can be leveraged to further study mechanisms of resilience to AD cognitive deficits and neuropathological damage that can be harnessed for better AD therapeutic treatments.
Choroid plexus protein turnover in human choroid plexus organoids recapitulates turnover in humans measured using stable isotope labeling kinetics (SILK)
Authors: Giovannucci Tatiana A. , Leckey Claire A. , Moncur Eleanor , Tariq Kanza , Thorne Lewis , Watkins Laurence , Toma Ahmed , Fox Nick C , Bateman Randall J. , Mills Kevin , Pellegrini Laura , Paterson Ross W.
Published: December 2023

Background

The choroid plexus secretes protein‐rich cerebrospinal fluid (CSF). CSF turnover is a key mechanism for protein clearance. Neurodegenerative diseases such as AD are characterised by accumulation of excess proteins that form pathological inclusions. CSF flow dysregulation could therefore be involved in the pathophysiology of neurodegenerative diseases (ND) such as Alzheimer’s Disease. A method for measuring CSF turnover in vivo may be achieved by quantitating CSF derived protein kinetics, providing a biomarker tool with to interrogate the relationship between CSF flow disequilibrium and neurodegeneration.

Method

Using untargeted proteomics we identify the most abundant proteins in a) stem‐cell derived choroid plexus organoids and b) human CSF. We then develop targeted mass spectrometry methods to quantitate protein specific peptides in both matrices. Using a stable isotope (13C6 leucine) we label a) choroid plexus organoids and b) humans with suspected NPH undergoing a 72 hour lumbar drainage protocol. We collect serial samples of the CSF‐like organoid fluid and CSF. We then measure the ratio of labelled to unlabelled peptides to quantitate the rates of protein labelling (fractional synthesis rate) and label loss (fractional clearance rate), defining the protein turnover rate.

Result

Highly‐expressed proteins in human CSF from nine individuals were also present in CSF‐like fluid from CP organoids. Of these common proteins, we were able to quantitate the turnover rates of transthyretin, apolipoprotein E, cystatin C and pigment epithelium‐derived factor, and the synthesis rates of serotransferrin and albumin. We will correlate these findings with clinical measures of CSF production.

Conclusion

Choroid plexus protein synthesis and clearance can be measured using SILK; choroid plexus organoid fluid protein turnover recapitulates that seen in human CSF.
Plasma IL‐6 levels are Negatively Associated with MRI‐Based Water Exchange Rate Across the Blood‐Brain Barrier
Authors: Pappas Colleen , Zachariou Valentinos , Bauer Christopher E. , Sudduth Tiffany L , Wilcock Donna M. , Shao Xingfeng , Wang Danny J.J. , Gold Brian T.
Published: December 2023

Background

Changes in blood‐brain barrier (BBB) integrity are associated with cognitive decline in aging. Inflammatory processes are thought to contribute to BBB dysfunction but this link has been difficult to measure in humans using non‐invasive, in‐vivo methods. Recently, a novel magnetic resonance imaging (MRI) technique, diffusion‐prepared arterial spin labeling (DP‐ASL), has been shown to provide a means to test the water exchange rate across the BBB (kw) as well as arterial transit time (ATT) and cerebral blood flow (CBF). Here, we tested the association between these DP‐ASL measures and a specific plasma marker of inflammation, IL‐6, in older adults without dementia.

Method

We tested the association between kw, ATT, and CBF and a marker of peripheral inflammation in a sample of 58 older adults without dementia. Regions of interest (ROIs) included the putamen, caudate, and pallidum. Plasma IL‐6 levels were assessed using Simoa assays. IL‐6 was natural log transformed and data collected ≤ 1 year from the MRI visit were used for subsequent analyses. Multiple linear regression models, controlling for age, sex, and ROI size, tested the impact of plasma IL‐6 on kw, ATT, and CBF metrics. Both linear and quadratic effects of IL‐6 on the outcomes of interest were examined.

Result

There was a negative linear association between IL‐6 and kw in the putamen. As plasma IL‐6 levels increased, kw values decreased. In contrast, no relationships were observed between plasma IL‐6 and ATT or CBF in any of the ROIs tested.

Conclusion

Our results suggest that the water exchange rate across the BBB in the putamen was most uniquely associated with the peripheral proinflammatory cytokine, IL‐6. These findings could be indicative of the involvement of peripheral inflammation in reducing glymphatic clearance which would manifest as reduced water exchange rate across the BBB. The lack of association with ATT and CBF suggest that peripheral cytokines could act on a mechanism more closely related to water channel function rather than overall brain perfusion.
Serine‐129 phosphorylation of α‐synuclein is a trigger for physiologic protein‐protein interactions and synaptic function
Authors: Parra‐Rivas Leonardo A , Madhivanan Kayalvizhi , Wang Lina , Boyer Nicholas P , Prakashchand Dube D , Aulston Brent D , Branes‐Guerrero Kristen , Rangamani Padmini , Roy Subhojit
Published: December 2023

Background

α‐Synuclein (α‐syn) phosphorylation at the Serine‐129 (Ser129P) residue is a recognized pathologic hallmark of PD. Though only ∼4% of α‐syn is phosphorylated at this site under normal conditions, the tight endogenous regulation of α‐syn Ser129P suggests a physiologic role.

Method

We have use immunocytochemistry in cultured hippocampal neurons and immunohistochemistry in mouse brains to localize α‐syn Ser‐129P, optical pHluorin assays to report SV‐recycling and trafficking, multielectrode arrays (MEA) to examine neurotransmitter release, immunoprecitations and GST Pulldown assays to evaluate protein‐protein interactions, and AlphaFold2‐driven modeling to visualize how Ser129P induces conformational changes.

Result

We found that unlike native (total) α‐syn that is widely expressed throughout the brain, the overall pattern of α‐syn Ser129P is restricted, suggesting intrinsic regulation and putative physiologic roles. Surprisingly, preventing phosphorylation at the Ser‐129 site blocked the ability of α‐syn to attenuate activity‐dependent synaptic vesicle (SV) recycling – widely thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments α‐syn Ser‐129P, and this phosphorylation is required for α‐syn binding to VAMP2 and synapsin – two functional binding‐partners that are necessary for α‐syn function. AlphaFold2‐driven modeling suggests a scenario where Ser129P induces conformational changes in the C‐terminus that stabilizes this region and facilitates protein‐protein interactions.

Conclusion

Our data from cellular, in vivo, cell‐free systems, and molecular simulations strongly suggest that the pathology‐ associated Ser129 modification has a physiologic role at the synapse, which has broad implications for α‐syn pathophysiology and drug development.
Plasma biomarkers, memory impairment, and imaging measures of Alzheimer’s disease in American Indians
Authors: Suchy‐Dicey Astrid M , Rhoads Kristoffer , Longstreth W.T. , Umans Jason G , Blennow Kaj , Buchwald Dedra , Grabowski Thomas J , Reiman Eric M. , Zetterberg Henrik
Published: December 2023

Background

Alzheimer’s disease (AD) is best defined in vivo using quantifiable, objective markers reflecting amyloid deposition (A), pathologic tau (T), and neurodegeneration (N). However, gold standards for ATN (imaging or cerebrospinal proteins) are expensive, invasive, and/or impractical in low resource settings. Circulating proteins offer a practical alternative. Candidate plasma markers include amyloid‐β (Aβ40&42), phosphorylated tau‐181 (ptau), glial fibrillary protein (GFAP), and neurofilament light chain (NfL). However, no such markers have been evaluated in American Indians.

Method

The Strong Heart Study recruited 401 American Indians over 3 states in 2017‐2019 for MRI, cognitive testing, and clinical examination. MRI included T1 sequences, which were processed using FreeSurfer to quantify structural volumes. Neuropsychological testing incuded California Verbal Learning Test, which was operationalized into categories of memory impairment using indices of learning and recall. Plasma samples were sent to University of Gothenburg for Simoa Quanterix assay. Statistics included descriptive summary; multivariate regression; and receiver operating characteristic analysis.

Result

The study population was mean age 78 (SD 4.7, range 70‐95); majority female (71%); and 21% APOE ε4 allele carriers. An estimated 31% had any memory impairment (13.8% retrieval, 6.5% storage, 10.7% encoding). Median plasma marker values were: ptau 5.0pg/mL (range: 1.5‐442), Aβ40 128pg/mL (116‐175), Aβ42 8.2pg/mL (6.7‐9.7), GFAP 150pg/mL (0‐651), and NfL 31.6pg/mL (9.7‐343); median Aβ42:40 ratio 0.06. Comparing APOEε4 carriers to non‐carriers (Table1), ptau was +12%, Aβ40 ‐0.8%, Aβ42 ‐8.4%, Aβ4240 ‐16.7% (P = 0.006), GFAP +16.1%, NfL +3.2%, but only Aβ4240 was significant. Linear regressions with brain volumes identified significant associations for Aβ42, Aβ40, GFAP, and NfL (but not ptau) with ventricle, cortical, and overall volume; NfL was also associated with entorhinal and hippocampal volume. GFAP and ptau were significantly higher in those with memory encoding deficit; NfL higher with encoding or retrieval deficit (Table2). Although not significant, Aβ40 was lower with storage deficit, and Aβ42 with encoding or storage deficit. AUC range for plasma markers to discriminate memory impaired from intact: 0.4‐0.6.

Conclusion

These data are a first look at ATN plasma markers in a population‐based cohort of American Indians, an underrepresented group in AD research. Future research should address generalizability and measurement validity.
Associations of Neighborhood Gentrification Status and Cognitive Decline in the Health and Retirement Study
Authors: Sims Kendra D , Willis Mary D , Bibbins‐Domingo Kirsten , Eng Chloe W. , Glymour M. Maria
Published: December 2023

Background

Gentrification, characterized by in‐migration of high socioeconomic (SES) residents into formerly disinvested neighborhoods, may impair late‐life cognitive function of existing residents. We hypothesized that disinvestment of neighborhood economic resources and reinvestment via gentrification both increase risk of cognitive decline among marginalized older adults.

Method

We analyzed 17,613 Health and Retirement Study participants (aged 51‐101), 67% Non‐Hispanic White) with data on our outcomes of interest: biennial scores on immediate and delayed word recall batteries (2010‐2016). With 2000 Census data, we operationalized census tract disinvestment based on disproportionately high proportions of minority residents, low SES, and renters for the corresponding county. We defined gentrification among disinvested tracts as greater than county‐median increases in White and college‐educated residents, household income, and housing costs between the 2000 Census and 2008‐2012 American Community Survey. We fit linear mixed models to evaluate associations of gentrification with cognitive level and change. We also evaluated racial‐ethnic differences in cognitive function by residence in tracts that were 1) not disinvested in 2000, 2) remained disinvested, or 3) gentrified by 2012. All models were adjusted by individual‐level age, gender, race‐ethnicity, educational attainment, marital status, home ownership, health insurance coverage, and memory score practice effects.

Result

56% of participants lived tracts that were disinvested in 2000; by 2012, 34% of disinvested tracts gentrified. Baseline memory performance was worse in invested (e.g., mean immediate = 4.9) than in initially disinvested tracts that either gentrified (mean = 5.3) or remained disinvested (mean = 5.4) (p<0.02 for test of mean differences). Neighborhood disinvestment from 2000‐2012 compared to investment in 2000 was associated with better 6‐year immediate recall trajectories among White participants (β; 95% CI: 0.18; 0.01, 0.39) but not among their Hispanic/Latino counterparts (‐0.14; ‐0.29, ‐0.01; p‐value for interaction compared to White participants = 0.04). We observed similar patterns for delayed recall (p‐value for interaction comparing Hispanic/Latino to White participants = 0.05). Neighborhood disinvestment or gentrification was not associated with recall trajectories among Black participants.

Conclusion

Differential findings by race in this nationally representative sample indicate that disinvestment and gentrification do not equally impact older adult cognitive health.
Herpes Simplex Virus‐1 Proteins Drive Alzheimer’s Disease Pathologies in Humans
Authors: Shemesh Or A. , Hyde Vanesa , Chattarjee Krishnashish , Zhou Chaoming , Fisher Greg , Pururav  , Lin Amanda , Caldwell Jill , D'Aiuto Leonardo
Published: December 2023

Background

DNA and RNA of Herpes Simplex Virus 1 (HSV‐1) were found in the brains and serological samples of Alzheimer’s disease (AD) patients. Such molecular presence of HSV‐1 in AD patients is especially intriguing as HSV‐1 virions are rarely detected in AD brains.

Methods

To follow the molecular footsteps detected, we imaged viral proteins in postmortem human AD brains at superior resolution using expansion microscopy, a tissue manipulation method that physically expands the samples by a factor of 4.5x, allowing a 40 nm imaging resolution, and immunolabeled herpetic proteins, AD pathologies and cell markers.

Results

We found an abundance of herpetic proteins, previously undetectable with standard methods, across large brain areas. Importantly, we found that HSV‐1 proteins strongly co‐localized with AD pathologies. Consequently, we hypothesized that expression of HSV‐1 proteins during latency may be linked to AD pathology. We are now in the process of characterizing the HSV‐1 proteome in AD brains by imaging key proteins in expanded AD brain slices and examining their colocalization with AD pathologies across brain areas and disease stages. As a complementary system to the fixed human brain slices, we introduced HSV‐1 in human derived brain organoids and imaged the relationships between viral proteins and the formation of AD pathologies via expansion microscopy. We found that HSV‐1 infection triggered these pathologies, pointing out that viruses may be triggers of immune responses driving AD.

Conclusions

this study sheds light on one common pathogen, HSV‐1, while serving as a framework to unveiling molecular causation between infectious agents and AD hallmarks.
Modifiers of Individual Differences and Within‐person Changes in the Aging White Matter
Authors: Burzynska Agnieszka Z
Published: December 2023

My talk will focus on: 1) longitudinal changes and plasticity, and 2) lifestyle and health modifiers of white matter (WM) health in aging.

First, individual differences in changes in WM microstructure may be key for identifying preclinical stages of dementia, opening new opportunities for early interventions. I will present the outcomes from a meta‐analysis and systematic review (Colmenares et al., in preparation) based on 28 diffusion tensor imaging (DTI) studies in healthy adults from the past 10 years, addressing the following questions: Over what time periods can decline in WM microstructure be detected using MRI? Do within‐person changes accelerate with age and vary by brain region? What are the modifiers of within‐person changes in WM? Also, for decades, adult WM has been perceived as a “passive” (i.e., only relaying electrical signals) and “static” (i.e., not capable of or involved in neuroplasticity). Despite emerging evidence in rodents on short‐term structural WM changes, evidence for such experience‐induced plasticity in adult humans remains inconclusive. Thus, I summarize evidence from clinical studies to discuss whether the adult WM microstructure is malleable with experience, and what interventions may be the most promising in inducing a change. I will also present our findings on exercise‐induced WM plasticity in older age, using DTI and T1/T2 ratio imaging (Colmenares et al., 2021, Burzynska et al., 2017).

Second, lack of physical activity (PA) and sedentary lifestyles are independently associated with increased risk of metabolic and cardiovascular diseases, mortality, and ADRD. Regular PA decreases inflammation and improves vascular function and perfusion. In contrast, insufficient PA and/or excessive sedentary behaviors is known to upregulate markers of metabolic stress and inflammation. I will briefly review our past work relating sensor‐measured PA with WM health, measured with DTI. Then, I will present our ongoing work using quantitative MRI, such as Myelin Water Imaging and Neurite Orientation Dispersion and Density Imaging. For example, I will present associations between systemic health (i.e., BMI, waist circumference, blood pressure, blood glucose and cholesterol), sensor‐measured physical activity (i.e., time spend sedentary and in light, moderate or vigorous physical activity), and myelin and axonal content in healthy adults.
Sex differences in functional network topological measures in the APP‐PS1 mouse model of amyloidosis
Authors: Simon Zachary D , Chakrabarty Paramita , Febo Marcelo
Published: December 2023

Background

Increased amyloid beta (Aβ) plaque deposition is linked to synaptic communication deficits in Alzheimer’s disease (AD). Functional deficits observed at the synaptic level are thought to alter neural communication across regions playing roles in cognition and affect. There is also growing evidence of a greater risk of AD in women, but the extent to which this involves differential responses to amyloidosis remains to be investigated. We tested the hypothesis that amyloid deposition alters functional network topology.

Method

Male and female mice (9‐month‐old) harboring human mutation amyloid precursor protein (Swedish APP KM670/671NL) and presenilin‐1 (PS1) (the APP‐PS1 [line 85] mouse) (Tg) and wildtype littermate controls (nTg) were tested on 3 consecutive days on a fear conditioning paradigm. On day 1, mice received training for 15 minutes using a series of 4 trials in the presence of an unconditioned stimulus (US) foot shock (0.90mA, 1 second) following a 20‐second conditioned stimulus (CS) tone (60dB). On day 2, mice received CS but not US in a ‘recall’ session. On day 3 the recall session was repeated with contextual cues modified. Following conditioning, mice were scanned on an 11.1 Tesla scanner under combined dexmedetomidine/isoflurane sedation using single shot echo planar images with echo time of 15 ms and repetition time of 1.5 seconds (600 total repetitions; 0.3mm2 in plane resolution, 0.7 mm slice thickness n = 17 slices). Images were processed and analyzed using nodes created on the common coordinate framework mouse atlas (version 3) and graph theory algorithms in brain connectivity toolbox.

Result

All mice developed robust CS freezing behavior, expressed during both recall sessions. Freezing behavior did not differ between Tg vs. nTg male and female mice. However, we observed significant differences in several measures of functional connectivity in APP‐PS1 mice that were driven by effects of amyloid in female mice. Compared to sex‐matched controls, female Tg mice had lower clustering, assortativity and node strength. These differences were not observed in Tg vs nTg males.

Conclusion

The results suggest that amyloid plaque burden reduces integration of neural activity (as measured by low clustering and assortativity) in female but not male APP‐PS1 mice.
Sleep breathing patterns and neurocognitive function in a diverse Hispanic/Latino cohort
Authors: González Kevin A , Tarraf Wassim , Kosik Eena , Guarian Kenton , Voytek Bradley , González Hector M , Ramos Alberto R
Published: December 2023

Background

Sleep disorders are common in patients with Alzheimer’s Disease (AD). Obstructive sleep apnea (OSA), characterized by intermittent cessation of breathing and hypoxemia, has been associated with increased risk of AD and worse cognitive function. However, the interacting effects of neurocognitive function with sleep breathing patterns, independent of the apnea‐hypopnea index, (a measure of OSA severity) have not been carefully studied. We use a novel approach to analyzing home sleep apnea data to examine breathing patterns and their relationships with neurocognitive function.

Method

The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a prospective multicenter study of diverse Latinos. Around 16,000 diverse Hispanic/Latinos were recruited from four major metropolitan cities. Participants used an ARES unirecorder device for a single night of unsupervised at home recording. We used python package “bycycle” to cannula data (sampled at 10Hz). Bycycle uses a time domain approach to parameterizing rhythmic time‐series data. We extracted breathing rate (breaths per minute), breathing variability (interquartile range of breathing rate) and time spent in inhalation phase (percent time). Participants ages ≥45 (unweighted n = 5,957) were tested in their preferred language using a brief battery including: B‐SEVLT (3‐trials sum) and Delayed Recall (memory), World Fluency (verbal fluency), and Digit Symbol Substitution (executive function). Covariates used in our models are described in Table 1. All presented estimates were weighted for appropriate generalization to the HCHS/SOL target population.

Result

In unadjusted models, all breathing measures were negatively associated with cognitive function, but only breathing rate remained significant after full covariate adjustment (Figure 1). We found significant interactions between breathing rate and sex, as well as age for verbal fluency models. Being female and older age were associated with steeper slopes of cognitive under‐performance for both breathing rate and breathing variability (Figure 2).

Conclusion

These results suggest that breathing patterns outside apneas‐hypopneas may be as critical in understanding sleep related changes and cognitive function in an aging population. Given cessation of breathing during an apnea‐hypopnea event, breathing variability may add more precision to account for varying oxygen demands. Further studies should examine whether breathing instability is also associated with cognitive decline, impairment, and dementia.
Hippocampal subfield volumes and memory performances: associations with stimulus modality and free recall or recognition
Authors: Aumont Etienne , Bussy Aurelie , Bezgin Gleb , Therriault Joseph , Savard Melissa , Arias Jaime Fernandez , Poltronetti Nina Margherita , Pallen Vanessa , Thomas Emilie , Vitali Paolo , Chakravarty Mallar , Bedard Marc‐Andre , Rosa‐Neto Pedro
Published: December 2023

Background

Age‐related memory decline is well associated with hippocampal atrophy, although the specific role of hippocampal subfields in memory function has not been thoroughly investigated yet. In this study, we investigated the associations between hippocampal subfield volumes and free recall and recognition performances in verbal and visual memory tasks in older adults without dementia.

Method

We selected 97 right‐handed participants without dementia aged 60 to 85, 42 males, from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. From T2‐weighted MRIs with 0.7*0.7*1mm voxel size, the hippocampi were segmented five subfields: 1) DG (DG); 2) CA2 with CA3 (CA2/CA3); 3) CA1; 4) strata radiatum, lacunosum and moleculare (SRLM); and 5) subiculum by using the MAGeT‐Brain algorithm. Memory was assessed with Rey Auditory Learning test for verbal free recall (RAVLT7) and recognition (RAVLT‐R), and with Aggie Figure Learning test for visual free recall (AFLT7) and recognition (AFLT‐R). Linear models were used to test the association between hippocampal subfield volumes and memory performances with age, sex and total intracranial volume as covariates (p<0.05, corrected for false discovery rate).

Result

The volumes of bilateral CA1 and SRLM were significantly associated with RAVLT7 and RAVLT‐R. The right DG volume was significantly associated with AFLT7 and RAVLT7. AFLT7 was also associated with the volume of right CA2/CA3 while AFLT‐R was not associated with any hippocampal subfield (see Figures 1 & 2).

Conclusion

Our results are consistent with the view that hippocampal subfields contribute differently to memory traces: CA1 for recollection that requires contextual information; the DG for pattern separation (creating new distinct representations of each stimulus); and CA3 for pattern completion (the recollection of a stimulus from a partial memory). Contextual information is more important when recollecting known words, while distinct and efficient encoding may be especially useful for search strategies inherent to free recall. Pattern completion could be particularly useful to efficiently recollect visual abstract figures based on visual features during free recall. Overall, this shows that hippocampal subfield segmentation offers a better understanding of their distinctive roles in cognition.
Feasibility of comprehensive heart‐brain MRI for investigating hemodynamic coupling in aging
Authors: Jarvis Kelly , Martersteck Adam , Richter Adam , Moore Jackson E. , Sridhar Jaiashre , Aristova Maria , Jin Ning , Schnell Susanne , Russell Eric , Markl Michael , Ragin Ann , Rogalski Emily J
Published: December 2023

Background

Cardiovascular risk factors have been linked with dementia risk in aging adults. However, mechanisms underlying heart‐brain hemodynamic coupling and effects on the brain remain unclear. 4D flow MRI is uniquely poised to systematically evaluate complex hemodynamics along the heart‐brain pathway. Owing to advancements yielding shorter scan times, 4D flow MRI can be acquired in approximately 7 minutes (heart) and 10 minutes (brain). This supports practical add‐on of 4D flow MRI to neuroimaging scans for comprehensive heart‐brain MRI evaluation in under an hour. We aimed to build a heart‐brain MRI acquisition and analysis framework to study relationships between hemodynamics and brain structure with age.

Method

17 healthy participants (age = 53.5±16.3[24‐76] years) underwent heart‐brain MRI at 3T (MAGNETOM Prisma, Siemens, Erlangen, Germany), including a free‐breathing whole‐chest 4D flow MRI research sequence, intracranial dual‐venc 4D flow MRI research sequence, and T1‐ and T2‐weighted structural neuroimaging. Participants were cognitively healthy and screened for history of cardiovascular and cerebrovascular problems that may influence blood flow. 4D flow MRI was used to evaluate blood flow velocities in the aorta and Circle of Willis (Figure 1: left). Mean velocity was determined on a voxel‐wise basis over the entire cardiac cycle. Volumetric and cortical thickness analysis was performed with FreeSurfer (v7.3; Figure 1: right). Left and right hippocampal and amygdala volumes were averaged and corrected for intracranial head size. We examined relationships between hemodynamics, volume and thickness measures, and age using Pearson correlations and multiple regression.

Result

Mean aortic velocity was associated with age (r = ‐0.59, p = 0.012), hippocampal volume (r = 0.68, p = 0.003), amygdala volume (r = 0.59, p = 0.012), and inferior temporal thickness (r = 0.49, p = 0.044). Figure 2. Mean velocity in the Circle of Willis (r = ‐0.49, p = 0.048), amygdala volume (r = ‐0.66, p = 0.004) and inferior temporal thickness (r = ‐0.60, p = 0.010) were also associated with age. Using multiple regression, mean aortic velocity was associated with hippocampal volume (p = 0.018) adjusting for age.

Conclusion

This study demonstrates capture of comprehensive heart and brain data in a single imaging exam for assessment of age‐related relationships in hemodynamics and brain structure. Heart‐brain MRI is a promising tool for evaluation of hemodynamic coupling along the entire heart‐brain pathway.

Grant support: NIH NIA P30AG059988, P30AG072977, K01AG080070; NINDS R21NS122511
ARKD‐104, A Potential Treatment of Frontotemporal Dementia and Other Neurodegenerative Disorders
Authors: Hung Serena W , Hurst Raymond S. , Blain Jean‐François , Holler Christopher J. , Chen Angela Y.P. , Brand Morgan A. , Alves Anna M , Astarita Giuseppe , Gallegos Richard , Greenberg Gennifer , Henry Shawna , Koenig Gerhard , McTighe Stephanie , Peng Xiaowen , Ross John , Thompson Bonne M , Watters Katherine , Wozniak Mary , Lanter James C. , Burnett Duane A.
Published: December 2023

Background

Heterozygous mutations in the gene encoding progranulin (GRN) that lead to haploinsufficiency of the progranulin protein (PGRN) cause the fatal neurodegenerative disease frontotemporal dementia (FTD‐GRN). A promising treatment approach for FTD‐GRN is to restore PGRN to levels detected in healthy individuals. In pursuit of this objective, Arkuda Therapeutics is developing brain‐penetrant, orally bioavailable small molecules that increase PGRN levels within the central nervous system (CNS).

Method

A functional cell‐based assay was utilized to identify novel compounds that stimulate PGRN secretion from a murine microglial cell line. Compounds with good in vitro potency were further optimized through an iterative series of selectivity, ADME, pharmacokinetic (PK), safety and pharmacology assessments.

Result

When applied to cells, ARKD‐104 increased PGRN and PSAP secretion and engaged lysosomal pathways as evidenced by intracellular changes in granulins, saposins, and lysosomal lipids including bis(monoacylglycero)phosphate (BMP). Oral administration of ARKD‐104 to cynomolgus monkeys resulted in a dose and exposure‐dependent increase in PGRN measured in cerebrospinal fluid (CSF). The exposure‐response relationship demonstrated that a systemic exposure of 8 nM ARKD‐104 in plasma (unbound) doubled the amount PGRN in CSF. PGRN levels were further increased to more than 4‐times pre‐dose levels at the highest tested dose. Elevation of PGRN levels was sustained with repeat dosing of ARKD‐104. ARKD‐104 was characterized for CNS drug‐like properties including PK, metabolism, brain penetration, selectivity, and safety. In these assessments, ARKD‐104 demonstrated a profile suggesting that beneficial increases in PGRN can be achieved with once daily oral dosing in human.

Conclusion

ARKD‐104 has excellent CNS drug‐like properties, increases PGRN in the CNS of non‐human primates and increases important cofactors of lysosomal enzymes, . ARKD‐104 is therefore a promising candidate for continued development as a treatment for FTD‐GRN, Parkinson’s disease and other neurodegenerative disorders exhibiting lysosomal dysfunction.
Afternoons can be a critical time of the day that reflects associations between life‐space mobility and loneliness among living alone older adults: longitudinal analyses with motion sensor data
Authors: Yu Kexin , Wu Chao‐Yi , Barnes Lisa L. , Silbert Lisa C , Beattie Zachary T , Dodge Hiroko H , Kaye Jeffrey A
Published: December 2023

Background

Daily activity patterns of life‐space mobility can serve as indicators for loneliness and subsequent cognitive change. Assessment of life‐space mobility often uses self‐reported data, and the measurement intervals are often less frequent than needed to capture change over time. This study examined whether the life‐space mobility changed when loneliness was reported weekly.

Methods

Participants were 139 older adults who lived alone (age = 78.1±8.6, 103 (74%) were female, 32 (23%) were African Americans, 19 (14%) had MCI diagnosis) and were enrolled in ORCATECH (ORegon Center for Aging & TECHnology) longitudinal aging studies and Minority Aging Research Study. Passive infrared motion sensors were placed in common rooms of each participant’s home (bathroom; bedroom; kitchen; living room). Time spent in each room across the day (morning; afternoon; evening; night) and out‐of‐home were used as indicators of life‐space mobility and were derived from home sensor data. Participants reported whether they felt lonely on a weekly basis using an online survey sent via email. Generalized estimating equations were used to correlate the time spent in each room and out‐of‐home and the likelihood of feeling lonely. Age, gender, education, race, cognitive status (MCI/ non‐MCI), and average daily time out‐of‐home were controlled in the model.

Results

We analyzed 4994 weeks of data; 232 weeks had an incidence of loneliness (5%). Spending an additional hour in the bedroom in the afternoon (noon‐6 pm) was associated with a 21% increase in the likelihood of experiencing loneliness (p = .03). Spending an additional hour out‐of‐home in the afternoon was associated with a 13% decrease in the likelihood of experiencing loneliness (p = .02). Time spent in the kitchen, bathroom, and living room in a day was unrelated to weekly loneliness.

Conclusion

Time spent outside the home may suggest an expansion of life‐space, while spending time in one’s bedroom may indicate contraction of life space. Our findings suggest carefully monitoring a person’s location in the afternoon might help detect loneliness in this population. Frequent and objective measurements of life‐space mobility can produce renewed insights into the experience of loneliness among older adults who live alone, and thus, inform timely interventions for loneliness and prevent cognitive decline.
Are Current International Pricing Paradigms for an Efficacious Disease‐Modifying Anti‐Alzheimer’s Treatment Equitable? Are Quality‐Adjusted Life‐Years Worth Considering?
Authors: Wilcox Charles S
Published: December 2023

Background

The June 2021 approval of aducanumab [Aduhelm], initially priced at $56,000/year, followed by the January 2023 approval of lecanemab [Leqembi], initially priced at $26,500/year, generated renewed debate over reasonable and appropriate pricing for disease‐modifying anti‐Alzheimer’s treatments. For equitable pricing of an anti‐Alzheimer’s treatment, what are the optimal patient‐centered pricing paradigms?

Method

A literature search of pricing models for anti‐Alzheimer’s, plus other, medicines indicates there are (at least) seven drug pricing models, with value‐based pricing being the most popular. In many countries new medicines are only compared within a certain indication, which may lead us to unknowingly pay substantially more for equal benefit in one disease versus another(1).

Result

In tandem with Leqembi’s expedited review and approval, there was substantial discussion as to what would be reasonable and appropriate pricing. Analysts at the Institute for Clinical and Economic Review [ICER] reported the drug would be cost‐effective at the $8,500 to $20,600 range; their analyses were based on preliminary data. Eisai analysts reported that lecanemab has a societal medicinal value of approximately $37,000, noting that it slowed cognitive decline by 27% over eighteen months(2). The top five selling drugs for multiple sclerosis have an average annual price of $64,760; the average annual cost for the top five cancer drugs is > $165,000.

Measurement of outcomes and costs are essential for value‐based pricing. For dementia, the International Consortium for Health Outcomes Measurement [ICHOM] notes that patient‐centered outcome measures represent the ultimate measure of quality and they are always multidimensional. Quality‐adjusted life‐years [QALYs] seem to be absent from the computation of pricing for anti‐dementia treatments. Although consensus on QALY calculations is evasive, currently extant data are compelling. In Australia, the 2023‐adjusted QALY range is $32,618 to $55,415; United Kingdom $49,631 to $98,158, Germany $25,562 to $82,079, Sweden $51,494 to $59,416 and in Japan $56,819 to $67,643(3‐5). Utilizing an 18‐month treatment‐period, a range of QALY valuations will be presented, plus comparisons with the two other clinical indications.

Conclusion

The inclusion of QALYs for valuation of Alzheimer’s disease medicines warrants consideration; and,

The full value of anti‐dementia treatments may be understated in current pricing models.
An implementation evaluation of the Driving and Dementia Roadmap (DDR) in Alzheimer Society organizations
Authors: Naglie Gary , Stasiulis Elaine , Sandhu Harvir , Gallucci Christina E. , Rapoport Mark J.
Published: December 2023

Background

In response to the immense challenges that people with dementia (PWD) and family/friend carers (FCs) face in the driving cessation process, we developed the Driving and Dementia Roadmap (DDR). The DDR is a web‐based resource comprised of information and tools to support PWD, FCs and healthcare providers in the decision‐making and transition to non‐driving. To understand the factors (i.e., barriers and facilitators) that influenced the DDR’s implementation in Alzheimer Society (AS) settings, we conducted an implementation evaluation.

Method

The DDR was implemented by AS staff in six organizations in four Canadian provinces. Nineteen AS staff were interviewed after a three to six month period of delivering the DDR to their clients. Participants also recorded details about each interaction involving the DDR (e.g., setting, mode and rationale). Data were examined using a thematic analysis approach guided by the Consolidated Framework for Implementation Research (CFIR), which is a meta‐theoretical framework comprised of constructs organized into five domains (e.g., user characteristics, intervention characteristics and process).

Result

The DDR was implemented mainly via individual consultations by telephone/email to FCs who expressed concern about driving issues. Main factors that facilitated the DDR’s implementation were related to the characteristics of the DDR, such as its perceived evidence strength (e.g., research‐based) and quality (e.g., variety of tools, association with reputable organizations), superiority to other resources (e.g., more in‐depth, comprehensive and user friendly) and its ease of delivery (e.g., via telephone/email with minimal instruction required by clients). AS staff characteristics’ that facilitated implementation included their enthusiastic and favorable views about the DRR’s potential to be an empowering resource that could facilitate conversations and early planning for driving cessation. Barriers to implementation included clients’ lack of computer skills as well as competing priorities for AS staff such as other projects and tasks, and attending to issues related to the COVID‐19 pandemic (e.g., isolation, caregiver burnout, staying safe).

Conclusion

This study highlights how the perceived strengths of the DDR resource itself and AS staff’s favourable beliefs about the DDR facilitated its successful implementation in AS settings. Strategies to address implementation barriers include offering a print‐based version of the DDR.
Cognitive Change in a Diverse Group of Individuals Aged 90+: The LifeAfter90 Study
Authors: Meunier Claire C. , Corrada María M. M. , Gilsanz Paola , George Kristen M , Glymour M. Maria , Kawas Claudia H. , Decarli Charles , Whitmer Rachel A.
Published: December 2023

Background

The oldest‐old are the fastest growing segment of the elderly population but very little is known about cognition in this age group; particularly in diverse populations. Our goal was to evaluate if domain specific cognitive change was different across different ethnoracial groups in those aged 90+.

Method

LifeAfter90 (LA90) is an ongoing cohort of participants aged 90+ who are long‐term members of Kaiser Permanente Northern California participants. Participants (n = 984) were interviewed every 6 months for up to 3.5 years (1‐7 visits). Executive Function (EF) and Verbal Episodic Memory (VEM) were measured every six months using z‐standardized Spanish English Neuropsychological Assessment Scale. Racial/ethnic identify (Asian, Black, Latino, or White participants) was used in linear mixed models with random slopes and intercepts adjusting for baseline age, gender, education, interview mode, and practice effects.

Result

Participants were 20% Latino, 23% Black, 24% Asian, 27% White, and 7% other individuals with a mean age of 92.4 (SD = 2.3) and a mean follow up time 1.1 years (Table 1). 39% of the cohort were men, 35% were college educated, and 29% were high school or less educated. Average annual change in EF was ‐0.06 (95% CI: ‐0.12, ‐0.00). Stratified models with Latino as the reference group showed White participants had significantly greater decline in EF (β = ‐0.13; 95%CI:‐0.20,‐0.06), followed by Asian participants (β = ‐0.09; 95%CI:‐0.17,‐0.01). EF scores among Black participants and participants who identified as other declined at a similar rate as Latino participants (β = ‐0.03; 95%CI:‐0.11,‐0.05; β = 0.00; 95%CI:‐0.10, 0.11; respectively) (Table 2: model 2). VEM had an annual change of ‐0.26 (95%CI: ‐0.40, ‐0.13), but there were no significant differences across ethnoracial groups in rate of decline.

Conclusion

In this population of individuals aged 90+, decline in EF over the study period varied across ethnoracial group with White participants experiencing the fastest decline and Black, Latino, and other participants experiencing the slowest decline. Continued follow up will identify if there are differences in risk of cognitive impairment in this diverse population of oldest‐old. The results suggest the disparities in cognitive aging for those aged 90+ don’t mirror disparities seen in younger‐elderly ages.