bluuebunny/crossref_metadata_2025 huggingface dataset:
Scholars reflect on first ADRC‐REC cycle
Authors: Spensley Sheryl , Bendlin Barbara B , Head Elizabeth , Cavazos José E. , Yassine Hussein N.
Published: December 2023

Background

In 2018, the National Institute on Aging introduced Research Education Components (RECs) within the Alzheimer’s Disease Research Centers (ADRCs) to support educational activities to complement the training of a workforce to meet the nation’s needs in AD and related dementias, and develop the next generation of scientists to lead cross‐disciplinary, translational, team‐science projects on AD or AD‐related dementias.

Methods

In April 2023, the ADRC REC National Steering Committee surveyed current and former REC scholars from the 37 ADRCs to learn about their experiences.

Results

We had responses from 26 of the 37 centers (70%) and 52 of the 55 REC scholars who completed the survey gave us permission to share their responses. Scholars ranged from graduate students to tenured faculty. The most common areas of research focus were basic or discovery science (42%) and neurosciences (35%). The least common areas of focus were social policy (2%), neuropsychology (2%) and pharmacology/drug discovery (6%). Regarding support, the most common responses were that their REC program provided them with funds to support a research project (79%), provided mentor support (71%), provided training to develop their research (65%), and helped them understand how Alzheimer’s Disease Research Centers worked (65%). Some scholars reported that their programs have standard training courses for all scholars (35%), while other programs have training that is unique to each scholar’s needs (54%). Forty‐nine scholars (94%) said they would have benefited from earlier REC support and training during their graduate and post‐doc stages.

A goal of the REC is to diversify the field of ADRD researchers. This survey showed the demographic breakdowns included White (52%), African American (13%), Hispanic or Latinx (13%), East Asian (12%), South Asian (8%), and some chose not to report (2%). More respondents identified as females (48%) than males (37%).

Conclusion

There is a heterogeneity of approaches to develop REC scholars with an emphasis on funding, mentoring and networking. The most common request from scholars was for more collaboration and networking between scholars from other ADRCs. REC Scholars seek more connections and clear definitions of the expected outcomes of the REC scholar initiative.
Astrocyte signaling regulates microglial and oligodendrocyte subpopulation changes in a diet‐based model of small cerebral vessel disease
Authors: Norris Christopher M. , Lee Sangderk , Gollihue Jenna L , Goulding Danielle S. , Sompol Pradoldej , Wilcock Donna M. , Morganti Josh M.
Published: December 2023

Background

Vascular contributions to cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzhiemer’s disease. Hyperhomocysteinemia (HHcy)‐inducing diets in mice recapitulate aspects of VCID including small cerebrovessel pathology, vascular inflammation and cognitive decline. Recently, we found signs of astrocytic Ca2+‐dysregulation and hyperactivation of calcineurin/NFAT activity in mice treated with HHcy diet (Sompol et al., 2023 J Neurosci 43:1797). Inhibition of astrocytic NFATs normalized cerebrovascular, synaptic, and cognitive function in HHcy mice, suggesting that reactive astrocytes alter the brain milieu during development of HHcy and small cerebrovessel pathology. Here, we used scRNA‐seq to further characterize the impact of astrocytic calcineurin/NFATs on multiple brain cell types in the context of HHcy.

Method

Seven‐to‐eight week‐old male C57BL/6J mice received intrahippocampal injections of AAV2/5‐Gfa2‐EGFP (control) or AAV expressing the NFAT inhibitor VIVIT (i.e. AAV2/5‐Gfa2‐VIVIT‐EGFP). Mice were then fed with control chow(CT) or HHcy‐inducing chow enriched in methionine and deficient in folate and vitamins B6 and B12. After15 weeks of diet, brains were extracted and hippocampi dissected away, pooled and dissociated for transcriptional analyses. scRNA‐seq was used to identify diet and AAV‐dependent cell specific gene expression changes according to our previous work (Lee et al, 2023, Cell Reports, 112196).

Result

31 cell clusters were identified and assigned to 1 of 12 unique cell types using established gene markers. Analysis of differentially‐expressed genes showed that microglia and oligodendrocytes were most sensitive to diet and/or AAV treatment. In HHcy mice treated with control AAV (HHcy–EGFP), predominant microglial subpopulations exhibited upregulation of several disease‐associated microglial genes (e.g. Apoe, Il1b, Ccl5, Cebpb, Cybb) and downregulation of common homeostatic genes (e.g. P2ry12, Gpr34, Fcrls, Sparc). Oligodendrocyte subpopulations in the same mice also exhibited upregulation of disease related genes (e.g. Serpina3n, H2‐D1, C4b, Klk6). However, these patterns were mitigated in HHcy mice treated with AAV‐Gfa2‐VIVIT, who exhibited expression patterns in line with CT diet mice. Analyses of DEGs in other cell types and association with immunometabolic pathways are in progress.

Conclusion

Results suggest that reactive astrocyte signaling strongly regulates molecular phenotypes of other local glial cells and provides a potential target for preventing/resolving pathologic glial activity in VCID and other ADRDs.
Distinct cultured microglia characteristics distinguish cognitive SuperAgers from their cognitively normal peers
Authors: Taefi Erfan , Bahrami Atousa , Garcia Donte , Ayala Ivan , Hickman Suzanne E , Gefen Tamar , Huentelman Matthew J , Mesulam Marsel , Rogalski Emily J , Khoury Joseph El , Geula Changiz
Published: December 2023

Background

SuperAgers are individuals ≥80 years with exceptional episodic memory equal to or better than individuals 20 to 30 years their junior. SuperAgers display resistance to age‐related neurofibrillary degeneration. Qualitative observations suggested that SuperAger cultured microglia display higher rates of proliferation compared to age‐matched controls. The purpose of this study was a comprehensive and quantitative investigation of potential differences between SuperAger and control microglia.

Method

Approximately 6.6×103 microglia from the frontal cortex of 5 SuperAgers and 5 controls were seeded and allowed to proliferate to 80% confluence prior to passage (P). Number of cells at confluence, number of days to confluence, and highest passage reached were recorded. Gene expression profiles were investigated in P4 cultures. RNASeq libraries were prepared using the Lexogen QuantSeq 3’ RNA Library kit and assessed using the Agilent High Sensitivity DNA chip. Bioinformatic analysis was performed using the BlueBee integrated data analysis pipeline. Microglia function was assayed through uptake of fluorescently tagged oligomeric and fibrillar amyloid‐β (Aβ42) and production of reactive oxygen species (ROS) in response to the two Aβ conformations.

Result

At each passage, SuperAger cultures contained greater numbers of microglia when compared with controls (by 150% at P5, p<0.01) and reached 80% confluent faster (by 108%). On average, control microglia ceased proliferating at P9, while SuperAger microglia proliferated up to P12. RNAseq analysis identified 434 genes differentially expressed in the two groups (p<0.05). Upregulated genes in SuperAgers included genes involved in DNA repair and in membrane trafficking. SuperAgers exhibited downregulation of several transcripts involved in age‐related disease pathogenesis, including Adap2, MAP2, RBM20, CNTN3, and genes that regulate mitochondrial oxidative burst. Preliminary functional analysis revealed more efficient uptake and response to oligomeric when compared with fibrillar Aβ. SuperAger microglia displayed greater ROS production when compared with controls. No differences were observed in Aβ uptake.

Conclusion

These results point to distinct characteristics of microglia that may contribute to the biological bases of the SuperAging phenotype. Upregulation of genes involved in DNA repair is likely to slow microglia senescence, allowing increased proliferation in SuperAgers. Additional studies are needed to validate and extend these findings.
Association of ambient air pollution with cognitive functioning and structural brain damage: The Maastricht Study
Authors: Soeterboek Jens , Deckers Kay , van Boxtel Martin P.J. , Backes Walter H. , Eussen Simone J.P.M. , van Greevenbroek Marleen M.J. , Jansen Jacobus F.A. , Koster Annemarie , Schram Miranda T. , Stehouwer Coen D.A. , Wesselius Anke , Lakerveld Jeroen , Köhler Sebastian
Published: December 2023

Background

Dementia prevention poses one of the biggest challenges to our ageing society (1,2). Next to individual modifiable risk factors, shared environmental risk factors have been linked to dementia risk. Exposure to air pollution has been identified as a new candidate risk factor which on a population level carries more risk than well‐established risk factors such as hypertension and type‐2 diabetes (1). This study aimed to investigate the association between exposure to air pollutants with cognitive functioning and markers of structural brain damage next to and above individual risk factors.

Method

Cross‐sectional data from the population‐based cohort (N = 4,154; mean age 59.27±8.54 years, 50.12% women) of The Maastricht Study (3) was used and matched to address‐based data from the Geoscience andHealth Cohort Consortium of average exposure to particulate matter (<2.5mg and <10mg), NO2 and soot over the years 2013‐2018. Cognitive functioning was assessed through a neuropsychological test battery. Standardized volumes of grey matter, white matter, cerebrospinal fluid, and presence of cerebral small vessel disease were derived from 3‐Tesla MRI. Individual risk factors were added as one covariate, using the validated Lifestyle for Brain Health score (4). Binary logistic and multiple linear regression analyses tested the associations between air pollutants and the outcome measures. Likelihood‐ratio tests were performed to compare the extensive models.

Result

We found a curvilinear association relating particulate matter exposure in the mid to higher range to lower grey matter and higher cerebrospinal fluid volume, independent of age, sex, education, and LIBRA score. There was no association between air pollutant exposure and cognitive functioning or markers of cerebral small vessel disease.

Conclusion

In this population‐based cohort, average to high exposure to particulate matter was related to an increase in markers of brain atrophy, showing important implications for environmental and public health policymaking.
Generalized Calibrated BOLD fMRI for the Relationship between Cerebral Metabolism and Hypertensive Status
Authors: Zhang Anqi , Kim Donghoon , Hong Sarah Y. , Hughes Timothy M. , Lipford Megan E. , Lockhart Samuel N. , Craft Suzanne , Baker Laura D , Whitlow Christopher T , Okonmah‐Obazee Stephanie E. , Hugenschmidt Christina , Bobinski Matthew , Jung Youngkyoo
Published: December 2023

Background

Elevated blood pressure levels during mid‐life have been found to be associated with an increased susceptibility to developing dementia later in life, particularly vascular dementia. Quantitative imaging biomarkers, such as Oxygen Extraction Fraction (OEF) and Cerebral Metabolism Rate of Oxygen (CMRO2), can be indicators of impaired cerebral metabolism. Calibrated Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) is a multi‐parametric approach utilizing hyperoxic and hypercapnic gas challenges (Figure 1). The impact of hypertension on OEF and CMRO2 has been investigated.

Method

A cohort of 84 participants was recruited from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core (Table 1). Among all the covariates, participants with prediabetes and diabetes were considered diabetic, and those who exhibited high blood pressure or were using medication to manage hypertension were classified as hypertensive. The MRI was conducted using a 3T Siemens Skyra MRI scanner with a 32‐channel head coil. Dynamic Pseudocontinuous Arterial Spin Labeling (PCASL) was used to acquire cerebral blood flow (CBF) and BOLD images during respiratory challenges with an end‐tidal forcing system. The ROI values in the frontal lobe, temporal lobe, parietal lobe, and occipital lobe regions were chosen. The correlation between hypertensive status and OEF and CMRO2 in the ROI was analyzed with a linear mixed model, with covariates of age, sex, cognitive status, APOE genotype, diabetic status, and hypertensive status.

Result

A negative correlation was found between CBF, OEF, and CMRO2 with hypertensive status in frontal lobe region (Figure 2). Statistical significance was observed for OEF and CMRO2 (p = 0.049 and p = 0.028, respectively), indicating the potential influence of hypertensive status on these biomarkers.

Conclusion

The study concludes that there is a significant negative association between hypertensive status and both OEF and CMRO2, particularly in the frontal lobe region. The observed reduction in OEF and CMRO2 is not solely due to decreased CBF, but rather complex and multifactorial processes involving vascular remodeling and altered oxygen metabolism. Additional research is necessary to fully understand the underlying pathophysiological mechanisms that link hypertension to decreased OEF and CMRO2, particularly in the context of regional specificity.
Significant dose‐dependent reduction in neurofilament light chain concentration in plasma with oral tau aggregation inhibitor hydromethylthionine mesylate
Authors: Wischik Claude M , Schelter Bjoern , Penny Lewis Kirk , Miller Sonya , Stefanacci Richard , Heslegrave Amanda , Zetterberg Henrik
Published: December 2023

Background

Hydromethylthionine mesylate (HMTM) is a potent oral tau aggregation inhibitor. Recent results from Study TRx‐237‐039 (LUCIDITY) suggest strong effects on cognitive and functional decline and progression of brain atrophy. We investigated the effect of HMTM on change in the plasma biomarker neurofilament light chain (NfL) in LUCIDITY. NfL is a clinically accessible and established biomarker for neurodegeneration that is known to be correlated with measures of clinical decline and brain atrophy in AD and MCI due to AD (MCI‐AD).

Method

LUCIDITY is a double‐blind randomised controlled Phase 3 clinical trial comparing change over 12 months in cognitive, functional and brain atrophy outcomes at HMTM doses of 16 mg/day, 8 mg/day and methylthioninium chloride (MTC) at a dose of 4 mg twice weekly as a control in a 4:1:4 randomisation, with a subsequent 12 month blinded open‐label extension phase in which all participants received 16 mg/day.

Result

Baseline and 12‐month NfL plasma levels were available as randomised in 161/185 participants receiving HMTM 16 mg/day, 38/48 receiving HMTM 8 mg/day and 136/185 receiving MTC 8 mg/week. The corresponding prespecified analysis model showed a 93% reduction in the change in NfL levels relative to control for HMTM 16 mg/day overall (p = 0.0278). Reduction in NfL change in the MCI‐AD subgroup was significant also at HMTM 8 mg/day (p = 0.0242). In the AD subgroup, there were directional dose‐dependent trends that did not reach statistical significance. Change in NfL level at 12 months was significantly correlated with change in ADAS‐cog11 (p = 0.0038) and whole brain volume (p = 0.0359) over 24 months.

Conclusion

These results demonstrate that the orally administered tau aggregation‐inhibitor, HMTM, is able to produce a significant dose‐dependent reduction in neurodegeneration in AD as measured by change in plasma NfL levels.
Predictors of Successful Brain Aging: An Autopsy Study
Authors: Iida Megan A , Marx Gabe , Kauffman Justin , McKenzie Andrew T , Koenigsberg Daniel , Richardson Timothy E. , Walker Jamie M. , White Charles , Farrell Kurt W. , Crary John F.
Published: December 2023

Background

The neuropathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques and neurofibrillary tangles, also accumulate in the brains of aging individuals. However, some individuals are able to age successfully without significant degenerative neuropathology or cognitive impairment, a phenomenon referred to as “successful aging”. The predictors of successful “neuropathologic” and “cognitive” aging are not fully understood, creating a critical knowledge gap. Factors such as resistance, resilience, and reserve are believed to play important roles. Furthermore, the relationship between neuropathological changes, such as tau pathology and amyloid pathology, and cognitive impairment in the oldest old population remains unclear, and the concept of amyloid plaques causing tau pathology may not be universally valid. The association between amyloid plaques and dementia also continues to be debated.

Methods

In this study, we utilized a collection of 414 post‐mortem brain tissues (171 female, 241 male) from aged individuals (average age 90, range 80‐108) with neuropathological and clinical data (215 without cognitive impairment and 161 with cognitive impairment) to perform a cross‐sectional analysis. Our cohort included subjects who had cognitive assessments available and included those with no amyloid plaque pathology or mild burden based on neuropathological criteria. Variables (including new traits derived from A.I. based feature extraction) associated with the cognitive measures were determined using multivariable logistic regression.

Results

Our results revealed that age of death and Braak neurofibrillary tangle stage were significant predictors of cognitive impairment (p<0.05), while amyloid positivity was not. These findings suggest that tau pathology may have a stronger association with cognitive impairment in the oldest old population compared to amyloid plaques.

Conclusion

Understanding the neuropathological factors associated with successful brain and cognitive aging will contribute to our knowledge of the underlying mechanisms and may pave the way for the development of interventions to promote successful aging and prevent cognitive decline in old age. Further research in this area is warranted to elucidate the complex relationship between neuropathology, cognitive function, and aging in the oldest old population.
Bio‐Hermes study topline results: Aß 40/42 and p‐tau181/217/231 blood‐based biomarkers compared to amyloid PET and CSF in a diverse, community‐based population
Authors: Beauregard Douglas W. , Gaudioso Jennifer , Mohs Richard , Hollingshead Sarah , Dwyer John , Bork Jason , Kerwin Diana R.
Published: December 2023

Background

Research of blood‐based biomarkers to indirectly assess amyloid presence in the brain has mainly been conducted in special populations (e.g., those enrolled in autopsy programs or single site populations selected for genetic vulnerability). To more accurately reflect clinical trial populations and to increase diversity, the Bio‐Hermes study used 17 sites and monitored recruitment to achieve ≥19% underrepresented minorities (URM) in each of the 3 clinical trial cohorts of Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and Mild AD. In addition to blood‐based biomarkers and the presence of amyloid plaques identified through brain amyloid PET and CSF, numerous digital tests and genetic assays were performed resulting in a robust Bio‐Hermes database.

Method

Within 18 months, 17 sites enrolled 1,001 participants (60‐85 y/o) in clinically defined cohorts of: CN (N = 417), MCI (N = 312), and Mild AD (N = 272). Traditional and digital cognitive testing, amyloid PET imaging, biospecimen collection, and speech analytics were performed. A subset of participants received a retinal exam. Blood biomarkers included Aß 42/40, p‐Tau181/217/231, NfL, GFAP, full genome sequencing, including APOE status, and proteomics. Digital biomarkers included memory recall, executive functions, and drawing‐based and speech elicitation tasks. Blood biomarkers’ relationship to amyloid PET was measured using Spearman’s rank correlation. A ROC curve analysis assessed the sensitivity and specificity of each biomarker and combination of biomarkers compared with amyloid positivity from PET and CSF.

Result

Brain amyloid positivity results were 21%, 34%, and 61% for the CN, MCI, and Mild AD cohorts, respectively. Initial data analysis by Global Alzheimer’s Platform Foundation® (GAP) compared results of blood Aß 42/40, t‐tau, and p‐tau181/217/231 tests with brain amyloid positivity. ROC analysis showed more favorable AUC for Aß 40/42 and p‐tau181 (0.8268), Aß 40/42 and t‐tau (0.7922), and Aß 40/42 (0.7918). For Black/African Americans, brain amyloid positivity was 24%, 23%, and 38% for the CN, MCI, and Mild AD cohorts, respectively, and for Hispanic/Latinos results were 4%, 37%, and 53%, respectively. Additional correlation and URM data will be available July 2023.

Conclusion

Initial topline results show blood‐based AD biomarkers are associated with brain amyloid positivity warranting further analysis of the Bio‐Hermes community‐derived database of blood‐based and digital biomarkers.
Spatial Extent as a more sensitive amyloid biomarker for early stages of Alzheimer’s disease
Authors: Farrell Michelle E. , Thibault Emma G. , Becker Alex , Price Julie C , Schultz Aaron P. , Properzi Michael J , Buckley Rachel F. , Jacobs Heidi I.L. , Hanseeuw Bernard J , Sperling Reisa A. , Johnson Keith A.
Published: December 2023

Background

Despite considerable advances in beta amyloid (Aβ)‐PET imaging over the last decade, the standard approach of estimating the average neocortical Aβ burden remains largely unchanged. However, as research and clinical trials increasingly shift earlier in the disease process, measures of how far Aβ has spread throughout the cortex (spatial extent) may prove more sensitive than average neocortical magnitude for detecting and quantifying early Aβ deposits and their association with future tau proliferation and cognitive decline.

Method

Clinically‐normal individuals (n = 214) were included from the Harvard Aging Brain Study with longitudinal PIB‐PET (2‐4 scans, median = 4.7±2.7 years) and annual cognitive data (median = 5.2±2 years), as well as a subset (n = 181) with flortaucipir (FTP)‐PET. Spatial extent (EXT) was computed as the number of cortical ROIs (n = 62, Desikan atlas) above their ROI‐specific threshold for Aβ positivity. EXT was compared to a traditional mean neocortical DVR using logistic growth modeling. Receiver Operator Characteristic (ROC) curve analyses evaluated EXT’s ability to identify baseline PIB‐ individuals (<1.19DVR/24CL) who progressed to PIB+ at 3‐year follow‐up. Linear Mixed Effects (LME) modeling assessed baseline EXT (or DVR) as a predictor of increasing inferior temporal tau (IT FTP SUVR) and cognitive decline on the Preclinical Alzheimer’s Cognitive Composite (PACC).

Result

EXT begins rising below the neocortical DVR threshold (Figure1A), reaching a maximal growth rate of 14 ROIs per 0.1 DVR increase (∼10CL) and plateauing as full cortical EXT is achieved starting at ∼1.5DVR/68CL. A 3‐ROI EXT threshold predicts progression from PIB‐ to PIB+ in 3 years (AUC = .97, SE = .82,SP = .97), outperforming neocortical DVR (AUC = .92, SE = .65,SP = .94, Figure1B). EXT provides a stronger biomarker of Aβ change than DVR (lower coefficient of variation, Figure2) across the Aβ continuum due to its low variance, even after EXT has plateaued. Baseline EXT is also a stronger predictor of increases in IT FTP SUVR (Figure 3A, η2
EXT = .25, η2
DVR = .20) and PACC decline (Figure3B, η2
EXT = .28, η2
DVR = .22).

Conclusion

By describing the spread of Aβ throughout the cortex rather than average neocortical Aβ burden, spatial extent provides a more sensitive measure of Aβ at early, preclinical stages of AD that may improve design of AD prevention trials and open new avenues for research into AD pathogenesis.
Glymphatic function maintains sleep‐sensitive cognitive performance and predicts overnight changes in plasma amyloid β in humans
Authors: Balkrishnan Shilpa , Giovangrandi Laurent , Vanderweerd Carla , Singh Tarandeep , Jaffe Michael , Lowenkron Jeffrey , Lim Miranda , Iliff Jeffrey J , Dagum Paul
Published: December 2023

Background

During sleep, the glymphatic system facilitates rapid exchange of fluid through brain tissues, clearing solutes, including amyloid β (Aβ), tau, and α synuclein that accumulate through the course of waking activity. Glymphatic clearance is widely believed to underlie the restorative effects of sleep on cognition, and its impairment is proposed to reflect the biological basis for the corrosive effects of sleep disruption. We sought to determine if glymphatic function or sleep EEG predicted changes in cognitive performance and overnight differences in Aβ biomarker levels using a new non‐invasive investigational medical device (IMD) to measure glymphatic function by dynamic impedance spectro‐tomography.

Method

Eighteen healthy 50‐65 y/o participants were enrolled in a cross‐over randomized control clinical trial encompassing one night of sleep and one night of sleep deprivation. Participants were instrumented with the IMD and overnight change in brain parenchymal resistance to flow, R, was measured. Sleep EEG powerbands, slow (0.4‐1Hz), delta (1‐4Hz), beta (15‐30Hz), and time spent in N2, N3 and REM sleep were derived from the device EEG. In both sleep and sleep deprivation interventions, cognitive tests (symbol digit modality test, SDMT; psychomotor vigilance test, PVT) were administered at 7am and blood Aβ biomarkers (Aβ40; Aβ42) were taken at 10pm and 7am.

Result

Overnight parenchymal resistance R predicted intraindividual paired differences (sleep – sleep deprivation) in cognitive test scores (A SDMT ρ = ‐0.65, p = 0.003; B PVT STD RT, ρ = 0.41, p = 0.095) and Aβ42 blood amyloid biomarker changes (C Aβ42 ρ = ‐0.53, p = 0.03; D Aβ40 ρ = ‐0.33, p = 0.21). Sleep EEG powerbands and time spent in N2, N3, and REM sleep were not predictive of sleep‐related changes in cognition or plasma Aβ biomarker levels.

Conclusion

Glymphatic function, measured continuously by dynamic impedance spectro‐tomography, predicted changes in the restorative effect of sleep on cognition and plasma Ab biomarker levels as hypothesized, but not previously demonstrated. In contrast, sleep EEG powerbands and time spent in N2, N3 and REM were not predictive. Detection of glymphatic impairment in real‐world settings may permit (i) early identification of individuals at‐risk for developing sleep‐related Alzheimer’s disease pathology, and (ii) enable precision targeted enhancement of glymphatic function to enhance glymphatic function and pathological protein clearance.
Functional Connectivity and White Matter integrity of intercommunity hub nodes in Subjective Cognitive Decline
Authors: Nowling Duncan , Bustos Nicholas , Barlis Katie L , Crull Jory , Lawson Andrew , Benitez Andreana , Jensen Jens H. , Dean Brian , Mintzer Jacobo , Joseph Jane E
Published: December 2023

Background

Subjective Cognitive Decline (SCD) is considered an early preclinical stage of Alzheimer’s Disease and related dementias (ADRD) which may show promise for targeted preventative treatments. Subtle changes in functional connectivity and white matter integrity (WMI) may occur in SCD. Few studies have applied both functional graph theory (GT) and diffusional kurtosis imaging (DKI) techniques in tandem to identify differences in vulnerable network hubs. We addressed these issues by applying GT and DKI to study differences in intercommunity brain hubs. The hypothesis was that in hubs identified in healthy controls, SCD subjects’ hubs would show decreased GT diversity coefficient (DC) and DKI mean kurtosis (MK).

Method

Images were acquired on a Siemens PRISMA scanner. Matlab was used to calculate DC and identify 5 hubs in 107 healthy controls (HC) and DC in 30 SCD (93 females, mean age = 67.51). SCD classification was determined by a comprehensive clinician evaluation or Everyday Cognition average item score>1.6, with objectively healthy cognitive performance (Montreal Cognitive Assessment score>22). Hub DC was the target in GLMM analysis, with diagnosis as predictor. Mean Kurtosis (MK) was analyzed in DSI Studio’s cross‐sectional connectometry using the hubs as seeds. Only the covariate of gray matter volume approached significance (p = .059), and was included in analysis. Mean age, education, head motion, and sex balance did not significantly differ between groups.

Result

All hubs had lower DC in SCD compared to HC (p ≤ .006). Connectometry identified positive correlation between MK and diagnosis in Left hemisphere tracts associated with two hubs: Inferior Fronto‐Occipital, Extreme capsule, and Uncinate tracts from Insular cortex, and Superior Longitudinal, Superior Corticalstriatal, Arcuate, Frontal Aslant, and Corticalspinal tracts from Middle Frontal gyrus.

Conclusion

Conclusion

Rs‐fMRI findings show that intercommunity functional hubs are weaker in SCD compared to healthy individuals. Furthermore, the study identified a relationship of higher MK values in SCD for hubs located in insular cortex and middle frontal gyrus, all left hemisphere biased. Higher MK in SCD also runs counter to our hypothesis but is supported by recent paradoxical increase theories of decline. WMI differences between groups may be subtler than functional changes, warranting examination of the 2 modalities’ relationship.
Peer group leadership for dementia health risk reduction
Authors: Hynes Mary T , Kastner Monika , Anderson Nicole D. , Astell Arlene J.
Published: December 2023

Background

With the worldwide number of persons with dementia predicted to triple by 2050 and a current lack of curative treatment [1], reduction of modifiable risks is increasingly important. In 2020 the Lancet Commission on Dementia, Prevention, and Care reported on twelve health risk management factors that could potentially reduce the risk of dementia [2]. Peer support groups have a history in supporting self‐management of health risk behaviour [3,4]. We wanted to learn if older adults have successfully provided peer leadership in group interventions for older adult health management.

Method

Using the Joanna Briggs Institute methodology for scoping reviews we searched three databases (Medline, Embase, and AgeLine) for articles describing older adult leadership for older adult health improvement in older adult health promotion or improvement groups. From the initial 16,000+ results, 19 studies met the criteria for full text screening and analysis.

Result

Of the 19 studies, 12 used peer leaders and seven had a reciprocal support model. For those using peer leaders, training varied from none to 30 weeks. Older adult leadership or reciprocal support occurred in a range of settings. There were studies examining an older adult run seniors centre and a supportive community engagement program. Six studies focused on diabetes or hypertension, conditions linked with dementia risks. Interventions lasted from four weeks to 24 years. No quantifiable patterns of health management were observed. The only pattern that emerges is that positive physical and behaviour changes occurred more often when peer leaders or co‐facilitators were expected to motivate or encourage participant engagement or mutual support and where expectations included participant goal setting behaviour. Most of the studies of 12 weeks or less did not see lasting changes.

Conclusions

When asked participants preferred and appreciated peer leadership; however, peer leadership itself was not sufficient for positive health changes. Research with a sharing and empowerment focus within groups often led to improved self‐efficacy and self‐management behaviours. Research with longer participant engagement may result in longer lasting health habits.
Economic burden of transitions to later stages of Alzheimer’s disease in Europe: elevating the sense of urgency to treat
Authors: Razavi Moaven , Herring William L , Gillis Cai , Pemberton‐Ross Peter , Maserejian Nancy Nairi , Nejati Mina
Published: December 2023

Background

Alzheimer’s disease (AD) significantly impacts individuals, families, and society worldwide. In Europe, it affects approximately 10 million people, leading to considerable healthcare costs, caregiver burden, and reduced productivity.1 It is crucial to slow down AD progression in order to alleviate the rising burden of the disease.

Method

Two targeted reviews were conducted, one on the prevalence of individuals with biomarker‐confirmed AD pathology and the other on the costs associated with AD by disease stage and care setting. The most recent prevalence1,2,3,4,5,6,7,8 and cost9,10,11,12,13,14,15,16,17,18 data were identified for selected countries, including the UK, France, Germany, Italy, Spain, Sweden, Netherlands, Finland, Switzerland, Estonia, and the Czech Republic. Regression‐based or linear extrapolation methods were applied to fill the existing data gaps where appropriate. All costs were converted to USD and adjusted for inflation to reflect 2022 values.

Result

The national costs associated with annual transitions across all AD stages were estimated to be ($11.4bn) in Germany, followed by France ($6.2bn), UK ($5.2bn), Spain ($3.7bn), Italy ($3.2bn), Switzerland ($1.9bn), Sweden ($1.4bn), Netherlands ($1.07bn), Finland ($0.8bn), Czech Republic ($0.7bn), and Estonia ($0.03bn). Early‐stage progression, with the largest number of individuals transitioning from mild cognitive impairment (MCI) to mild AD, accounted for more than half of the total transitioning costs in the UK, Spain, Finland, Netherlands, Czech Republic, and Estonia. However, the highest cost burden varied across the countries. In Germany, Italy, and Switzerland, similar to previous estimates for the US,19 the highest burden was associated with late‐stage progression from moderate to severe dementia, despite the relatively lower number of such transitions. This is likely due to the more expensive institutional care in these countries. Our findings further suggest that including the economic value of uncompensated caregiving substantially increases the total costs while leading to greater variability in estimates. The interpretation of these results should take into account data limitations and the assumptions made in the analysis.

Conclusion

The economic burden of AD increases as disease progresses. Total costs and the underlying components vary across health systems and regions. Nevertheless, universally, any treatment that slows down the disease progression could result in substantial costs savings.
Treating microRNA dysregulation in AD mice models: A systematic review
Authors: Salcido‐Montenegro Alejandro , Quintanilla‐Sanchez Carolina , Leroy Karelle
Published: December 2023

Background

Efficient treatments for Alzheimer’s disease are still not available. As miRNAs are becoming therapeutic targets, a critical review of the evidence in AD mice models is required.

Method

This is an ongoing review, following the recommendations of PRISMA guidelines. The search was conducted in in MEDLINE, Scopus and ProQuest. Only peer reviewed interventional studies of in vivo AD mice models are eligible. Information about model, intervention, targeting miR and efficacy measures is being extracted.

Result

From the 5239 retrieved studies, 10 have been completely reviewed. The most common targeting miRNA is miR‐146a, followed by miR‐124, miR‐30b and miR‐138. Cognitive impairment was rescued by intracerebral injections of miR‐146a antagomir (Islam et al., 2021; G. Wang et al., 2016), inhalation of a chemically modified 146a mimic (Mai et al., 2019), by environmental enrichment (Nakano, Kubota, Hashizume, et al., 2020) and by the intracerebral injection of bone‐marrow derived mesenchymal cells (Nakano, Kubota, Kobayashi, et al., 2020). Molecular mechanisms involved are decrease in neuroinflammation and tau phosphorylation and an increase in the synaptic density. Antagomirs of miR‐124 in the Tg2576 and P301S models, improve memory deficits, while improving synaptic density and function and decreasing tau‐phosphorylation and aggregation, respectively (Hafez et al., 2021; X. Wang et al., 2018). However, mice injected with oA42i, reported a downregulation of miR‐124 and intervention with 3,4‐dihydroxyphenylethanol produced a behavioral improvement as well (ArunSundar, Shanmugarajan, & Ravichandiran, 2018). miR‐138 and miR‐30b antagomirs decreased memory deficits by means of synaptic morphology and function improvement in the 5XFAD and APPswe/PSEN1dE mice (Lu, Tan, & Wang, 2019; Song, Hu, Zhang, Teng, & Chen, 2019). Nevertheless, the longest incubation time was 1 month and in any of the studies the intervention was repeated. No side effects were reported.

Conclusion

Several interventions targeting miRNAs are emerging and although positive effects are seen in the short run, longer observation times are needed. The molecular mechanisms under the effect of miRNAs are complex, as shown by the beneficial effects of both agonists and antagonists of miRNA‐146a. More studies are needed to elucidate the main mechanisms and the most adequate therapeutic approach.
In what ways can digitally mediated epistemic practice enable organisational learning in dementia care practice?
Authors: Bartle Caroline B
Published: December 2023

Dementia Care is highly skilled work. Delivering person centred care requires an understanding of multiple bodies of knowledge combined with situated knowledge of the person in their environment. However traditional training methods often fall short, with limited learning transfer to practice. Training is often developed to meet mandatory requirements, but often lacks local contextual knowledge essential for learning transfer. ‘Standard’ programmes often provide limited opportunity to develop skills to meet the diverse range of needs typically found within a dementia care service. Ineffective learning systems are common and can lead to systemic problems where skills deficits and poor practice become embedding, escalating costs for care organisations.

New approaches that utilise data to level technologically driven solutions for more effective workforce planning are required. Education technologies that enable learning in the flow or work alongside data derived from digital care planning systems can be used in intelligent ways to design and enable rapid, responsive learning in practice. Workforce development data delivered in real time enables practitioners to adapt their approach. For example, that enable reflective practice can counteract the impacts of emotional labour and tackle unconscious bias. However, how can this work effectively and what are the risks? What opportunities does technology provide to support staff wellbeing? What are the opportunities and limits of utilising data? For example, data driven feedback loops may minimise, or indeed eradicate opportunities for deep learning.

The presentation will summarise the initial literature review exploring how epistemic practices evolve in dementia care services to enable organisational learning considering:

In what ways do different data practices impact organisational learning?

How do blended approaches impact epistemic practices?

What opportunities might there be for digitally mediated practices to improve dementia care?
Precision Recommendations to Optimize Neurocognition [PREVENTION] Trial: Preliminary Results
Authors: Merrill David A. , Bramen Jennifer E. , Hodes John F. , Rapozo Molly K. , Glatt Ryan M. , Ganapathi Aarthi S. , Wong Claudia L. , Porter Verna R. , Kim Mihae , Tongson Ynez M. , Bookheimer Tess Helen , Popa Emily S. , Meysami Somayeh , Nomura Natsuko , Choden Pema , Dye Richelin V. , Togashi Tori , Loong Spencer , Panos Stella E. , Miller Karen J. , Siddarth Prabha , Roach Jared C.
Published: December 2023

Background

Alzheimer’s disease (AD) is a complex neurodegenerative condition that requires a comprehensive treatment approach. In addition to pharmacologic treatment, managing existing medical conditions and incorporating lifestyle modifications, such as diet, cognitive training, and exercise, are potentially crucial components of an effective intervention. In this study, we present preliminary results of a personalized multi‐modal intervention for AD.

Methods

The Precision Recommendations to Optimize Neurocognition (PREVENTION) study is an ongoing 12‐month randomized clinical trial. Fifty participants (mean age 71.9(SD = 7.2); 24 Female) with biomarker evidence of AD amyloidosis have been recruited. While both arms receive personalized data‐driven, lifestyle recommendations designed to target multiple systemic pathways implicated in AD, the active arm also receives health coaching, dietary counseling, exercise training, cognitive stimulation, and nutritional supplements. Comprehensive clinical, cognitive, neuroimaging, and genetic data are collected at baseline, and post‐intervention. Herein, we examined the effects of the intervention on global cognition (MoCA) and regional brain volumes using general linear mixed models and compare to literature values (or historical controls).

Results

Participants in the two groups (23 active; 27 control) did not differ significantly in demographic, cognitive, or brain imaging measures at baseline. Thirty‐one participants (16 active; 15 control) have completed the study. Within‐group 12‐month changes in MoCA (active:‐1.4(3.5); control:‐1.7(3.6)) were not significant, did not differ significantly between groups and were borderline (p = .08) less than expected rate of decline. While both groups declined significantly in hippocampal volumes, percent changes in total gray matter, entorhinal cortex, and precuneus volumes were significantly less in the active arm (Table).

Conclusion

In this preliminary analysis of an active multimodal lifestyle intervention paired with personalized health optimization, regional volume loss in certain key areas of interest in AD was significantly lower in the active arm compared to control; further, the decline in global cognition was not statistically significant and was attenuated for the entire cohort compared to literature values. These preliminary results in a relatively small cohort suggest the intervention may beneficially impact cognition, memory, and brain structure. Future analyses will focus on elucidating changes in the biological systems being targeted by the intervention to help uncover the underlying mechanisms.
Peripheral and Central Nervous System Immune Effects of Bacillus Calmette‐Guérin (BCG) Vaccination in older adults with and without cognitive impairment
Authors: Kodali Mahesh Chandra , Young Katie , Kivisäkk Pia , McManus Alison J. , Gerber Jessica A. , Faustman Denise L. , Weinberg Marc S. , Arnold Steven E. ,   Massachusetts General Hospital Alzheimer’s Clinical and Translational Unit
Published: December 2023

Background

The live‐attenuated vaccine Bacillus Calmette‐Guérin (BCG), is widely used for the prevention of tuberculosis, and has myriad non‐specific beneficial effects in T1DM, multiple sclerosis, decreasing all‐cause childhood mortality, etc. Alzheimer’s Disease (AD) is a complex neurological disease. The innate immune system, intimately involved in the early and late phases of AD, may prove an ideal target for mono‐ or multi‐pronged therapy against AD. Data from multiple population health studies find that BCG treatment for bladder cancer is linked with decreased incidence of AD. Preclinical data also supports an AD‐beneficial effect of the vaccine. While mechanisms of some of these non‐specific vaccine effects have been elucidated, the mechanism behind BCG’s putative central nervous system (CNS) benefits is unclear. Here, we conducted a pilot open‐label study of the BCG (Tokyo strain) in the older adults to study CNS beneficial effects, particularly as they pertain to AD.

Methods

Baseline measures of participants (N = 16) with or without mild cognitive impairment (MCI) included cognitive and neuropsychological testing, phlebotomy, and lumbar puncture (LP), followed by an initial intradermal BCG, with a booster given 1mo later. Neuropsychological testing, phlebotomy and LP were repeated at 3mo, 6mo (no LP), and 12mo. The primary endpoints include 1) the safety of the vaccine in older adults and 2) target engagement. Secondary and exploratory endpoints include 1) functional, immunological, and AD‐related biomarker measures and 2) cognitive and neuropsychological effects.

Results

Our interim analysis demonstrated an overall improvement in repeatable battery for neuropsychological status (RBANS) total score index (TSI), notably in subsections of delayed recall, and visuospatial and constructional indices. Our results also show robust peripheral target engagement and the induction of trained immunity in the peripheral blood cells. We will further show the effects on various AD‐related biomarkers in plasma and cerebrospinal fluid.

Conclusion

These findings support that the BCG vaccine is safe in older adults and may improve cognition (enrollment of a placebo control group is underway). A further study including subjects with MCI and AD is ongoing. Our interventional studies with BCG begin to explore whether this strategy of retraining the neuroimmune axis can prevent and/or treat AD.
Subjective language difficulties are associated with tau and objective verbal memory in older women with increased AD risk
Authors: Lui Kitty K , Wang Xin , Dratva Melanie A , Heyworth Nadine , Shepherd Alyx L , Bernier Rachel A , Danish Madina , Ahmadi Nargis , Galasko Douglas R. , Sundermann Erin E. , Banks Sarah J
Published: December 2023

Background

Early cognitive changes in preclinical Alzheimer’s Disease (AD) include memory problems and language difficulties. Subjective cognitive complaints (SCC) are an AD risk factor and are associated with AD pathologies. Women have higher tau levels over men, despite demonstrating a life‐long “verbal memory advantage.” Therefore, SCC may be a stronger indicator of early tau accumulation than objective cognitive changes. Here, we examined the relationships among tau, subjective cognitive function, and objective cognitive function in older women at higher AD risk.

Method

16 older women (age: 72.3±3.1years) participated in Women Inflammation and Tau Study (WITS). The inclusion criteria are: 65+ years old, AD polygenic hazard score >50th percentile, and a telephone Montreal Cognitive Assessment score suggestive of mild cognitive impairment (MCI; range 16‐20). Tau was measured with cerebrospinal fluid (CSF) ptau181 and 18F‐MK6240 positron emission tomography (PET) with standardized uptake value ratio (SUVR) calculated in Braak1, correlating with MCI stage. Objective memory and language performance were assessed with the Rey Auditory Verbal Learning Test (RAVLT; immediate and delayed recall) and the Multilingual Naming Test (MINT), respectively. Subjective cognition was measured approximately one year later with the self‐reported Everyday Cognition Scale (ECog) memory and language subscales (higher score indicate more complaints). Spearman partial correlations analyzed the associations among tau, objective cognition, and subjective cognition while controlling for age.

Result

Greater CSF ptau181 was significantly associated with higher ECog‐Language (rho = 0.62, p = 0.02), higher ECog‐Memory (rho = 0.53, p = 0.51), and lower RAVLT immediate recall (rho = ‐0.54, p = 0.046; Figure 1). More tau in Braak1 was associated with lower RAVLT immediate recall (rho = ‐0.58, p = 0.03) and higher ECog‐Language (rho = 0.45, p = 0.09), but not ECog‐Memory (p = 0.26; Figure 2). Higher ECog‐Language was significantly associated with lower RAVLT immediate (rho = ‐0.59, p = 0.02) and delayed recall (rho = ‐0.69, p<0.01; Figure 3). MINT correct responses were not related to tau and ECog (p’s>0.28).

Conclusion

Our preliminary results suggest that, in older women with elevated AD risk, language concerns with memory features (e.g., word finding and forgetting object names) may track with early increases in CSF ptau181 and entorhinal cortex tau‐PET. Self‐reported language decline may be predictive of tau accumulation and worsening objective verbal memory, which could be clinically important for older women.