bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of initial symptoms of prodromal familial Frontotemporal Lobar Degeneration: Data from the ALLFTD Consortium
Authors: Miyagawa Toji , Brushaber Danielle , Kremers Walter K. , Fields Julie A. , Forsberg Leah K. , Heuer Hilary W. , Huey Edward D. , Knopman David S. , Kornak John , Boxer Adam L. , Rosen Howard J. , Boeve Brad F. ,   ALLFTD Consortium
Published: December 2023

Background

The ALLFTD Consortium aims to characterize preclinical and prodromal stage of familial Frontotemporal Lobar Degeneration (f‐FTLD) to prepare for clinical trials in FTLD.

Method

We prospectively followed 320 asymptomatic participants of the ALLFTD Consortium who are family members of f‐FTLD with a mutation in MAPT (n = 106), GRN (n = 74), or C9orf72 (n = 140), and describe the ratings on the eight domains of CDR® plus NACC FTLD (FTLD‐CDR) in those who phenoconverted to Mild Behavioral and/or Cognitive Impairment (MBCI). MBCI was diagnosed by the proposed research criteria for MBCI‐FTD (Barker MS, et al. Brain 2022). Participants who were diagnosed as MBCI but returned to asymptomatic at the following visit were excluded from the FTLD‐CDR assessment. ANOVA was used to compare continuous variables, and chi‐square test was used to compare categorical variables across the groups.

Result

Thirty‐six participants (15 MAPT, 9 GRN, 12 C9orf72) developed MBCI during follow‐up visits, 13 participants (5 MAPT, 3 GRN, 5 C9orf72) were diagnosed as MBCI but were characterized as asymptomatic at the following visit, and 271 participants stayed asymptomatic. Percentage of male in MBCI participants was 50% (MAPT 60%, GRN 33%, C9orf72 50%, p = 0.45). Age at phenoconversion to MBCI was 53.6±13.0 years old, the youngest in MAPT and the oldest in GRN participants (MAPT 44.3±8.3, GRN 63.1±11.3, C9orf72 56.4±10.8, p<0.001). Abnormal rating on each of the eight CDR® plus NACC FTLD domains at the initial visit of MBCI phenoconversion were observed in: “Memory” 36% (MAPT 33%, GRN 33%, C9orf72 44%, p = 0.95); “Orientation” 8% (MAPT 7%, GRN 8%, C9orf72 11%, p = 0.93); “Judgment/Problem Solving” 44% (MAPT 47%, GRN 50%, C9orf72 33%, p = 0.73); “Community Affairs” 22% (MAPT 27%, GRN 17%, C9orf72 22%, p = 0.82); “Home/Hobbies” 25% (MAPT 40%, GRN 8%, C9orf72 22%, p = 0.16); “Personal Care” 0%; “Behavior/Comportment/Personality” 44% (MAPT 60%, GRN 42%, C9orf72 22%, p = 0.19); “Language” 31% (MAPT 13%, GRN 50%, C9orf72 33%, p = 0.12).

Conclusion

The three most common FTLD‐CDR domains initially disturbed in the prodromal stage of fFTLD were “Behavior/Comportment/Personality”, “Judgment/Problem Solving”, and “Memory”, while “Orientation” was intact in the majority of the individuals. Memory impairment without disorientation was seen in one‐third of the prodromal fFTLD participants.
Study Design of FINGER‐NL: a Multidomain Lifestyle Intervention in Dutch Older Adults to Maintain Optimal Cognitive Functioning
Authors: Deckers Kay , Zwan Marissa D. , Soons Lion M. , Waterink Lisa , Beers Sonja , van Houdt Sofie , Meijer‐Krommenhoek Yvonne , van Pelt Hilde , Claassen Jurgen A.H.R. , Oosterman Joukje M. , de Heus Rianne A.A. , van de Rest Ondine , Smidt Nynke , Broersen Laus M. , Counotte Danielle , Sikkes Sietske A.M. , van Boxtel Martin P.J. , Aarts Esther , Köhler Sebastian , van der Flier Wiesje M.
Published: December 2023

Background

Evidence on the effectiveness of multidomain lifestyle interventions to prevent cognitive decline in non‐demented older individuals is mixed. The multidomain FINGER study1 found small positive effects on cognition among older people at risk for dementia. As part of the World‐Wide FINGERS initiative to replicate and build on these results, FINGER‐NL aims to investigate the effectiveness of a 2‐year high versus low intensive multidomain lifestyle intervention on cognitive functioning in Dutch older at‐risk individuals.

Method

FINGER‐NL is a Dutch multi‐center, randomized, controlled, multidomain lifestyle intervention trial aiming to include 1,206 adults at risk for cognitive decline. Adults aged 60‐80 years with at least 3 modifiable dementia risk factors (based on ‘LIfestyle for BRAin Health’ (LIBRA))2 and either a family history of dementia or self‐reported cognitive decline are eligible for inclusion. Participants are randomized (1:1 ratio) to either a high (HI‐group) or low‐intensity (LI‐group) intervention group. The multi‐domain intervention comprises a combination of 7 lifestyle components (physical exercise, cognitive training, cardiovascular risk management, nutritional counseling (with a specific focus on the MIND diet), sleep counseling, stress management, social activities) and 1 nutritional product (Souvenaid, 125ml). The HI‐group receives a personalized, supervised and hybrid intervention consisting of group meetings and individual sessions guided by a lifestyle coach. The LI‐group receives online lifestyle‐related health education. Primary outcome is 2‐year change from baseline on the cognitive composite score covering processing speed, executive function and memory. Secondary outcomes including changes in specific cognitive domains, instrumental activities of daily living, LIBRA score, and lifestyle component specific outcomes. For recruitment, we use the Dutch Brain Research Registry.3

Result

Participant recruitment started in January 2022. So far, 2405 people were interested, 1711 individuals have been screened for eligibility, 949 underwent baseline testing and 880 participants (73% of target sample) have been randomized and started with the intervention. The intervention is well‐accepted based on drop‐out rate (0.5%) and use of the online intervention portal. We expect to finalize randomization in Q2 of 2023 and complete the two‐year trial in 2025.

Conclusion

Results so far show that FINGER‐NL is well on track, the intervention is well‐accepted and the trial will reach its inclusion target.
Sex / gender bias on the Face‐Name Associative Memory Exam in clinically‐normal older adults
Authors: Lu Kirsty , Nicholas Jennifer M , Street Rebecca E , James Sarah‐Naomi , Fox Nick C , Richards Marcus , Crutch Sebastian J , Schott Jonathan M
Published: December 2023

Background

Many studies of memory in older adults report a sex difference, usually with female participants scoring slightly better than males. These sex differences may be partially due to the content of the tests, with some content being more memorable to males or females (https://doi.org/10.1093/ARCLIN/ACAC102). We investigated whether male and female older adults show differences on the Face‐Name Associative Memory Exam (FNAME‐12, designed to detect subtle Alzheimer’s disease‐related memory impairment). Specifically, do they show a bias towards remembering the stimuli that match their own sex?

Method

Participants (n = 432, see Table 1) in ‘Insight 46’, a sub‐study of the MRC National Survey of Health and Development (British 1946 birth cohort), completed FNAME‐12 (version A) at age ∼73 years. Stimuli comprise six male and six female faces (presented in alternating order), with names and occupations. Recall is tested four times after various delay intervals. Four total scores were calculated across all recall trials: female names; female occupations; male names; male occupations. We fitted multivariable regression models using Generalised Estimating Equations to investigate effects of item type (name/occupation), item gender (male/female) and participant sex (male/female), and interactions between these variables, controlling for age, education, socioeconomic position and prospectively‐collected childhood cognitive ability.

Result

Women outperformed men (coefficient averaged across the four conditions = 2.2 points [95% CIs 1.3, 3.1], p<0.001) (Fig1; Fig2). This difference was exaggerated for female stimuli (interaction coefficient = 2.0 [1.4, 2.6], p<0.001), and female stimuli occupations (3‐way interaction coefficient = 0.8 [‐0.0, 1.6] p = 0.050) i.e. women scored better than men even on male names, whereas men were particularly disadvantaged at recalling information associated with female stimuli, especially their occupations (Fig2).

Conclusion

We found evidence of a gender bias on FNAME‐12 among male participants, where their recall was worse for female stimuli compared to male stimuli, which may partially explain their poorer performance on this test. Such biases should be considered when interpreting sex differences on memory tests. Further analyses before the conference will investigate longitudinal FNAME‐12 performance over ∼2.4 years, to explore whether this memory bias remains constant, or whether it may be a marker of memory decline (potentially reflecting increased reliance on the relatability of test content).
Novel Increase of N‐ and O‐linked Sialylation in Alzheimer’s Disease
Authors: Fastenau Caitlyn , Wickline Jessica L , Smith Sabrina , Odfalk Kristian F , Hopp Sarah C. , Bieniek Kevin F
Published: December 2023

Background

Research shows evidence of increased sialylation in post‐mortem Alzheimer’s Disease (AD) cases. Sialylation is a form of glycosylation with the attachment of N‐acetyl‐neuraminic acid or sialic acid (SA) to glycoproteins and lipids. There are two major forms of sialylation, N‐ and O‐linked SA, modifications that regulate microglia cellular interactions and immune response. Yet it is unclear how these forms of sialylation contribute to AD pathology and modify disease progression. We hypothesize specific microglia sialylation patterns early in disease progression contribute to pathological burden and dampen immune response.

Methods

We utilized brain tissue from 10 post‐mortem human AD cases, focused on frontal, hippocampal, and cerebellar regions, and 5XFAD mouse model of amyloid pathology. To Identify N‐linked SA bonds, we focused on α‐2,6 SA which was recognized by a plant‐derived lectin. Aβ plaques, neurofibrillary tangles, microglia, and α‐2,6 SA were labelled with immunofluorescent markers in cortical brain tissue. Samples were imaged with confocal microscopy. To identify O‐linked SA bonds, Alcian Blue and Periodic Acid Schiff stains were used in novel ways to differentiate subsets of neutral and charged O‐linked SA bonds. Samples were imaged on a Aperio microscope slide scanner.

Results

12‐month‐old 5XFAD mice have significantly higher percent of α‐2,6 SA coverage in the plaque microenvironment compared to WT littermates (p<0.001). Pearson correlation analysis determined significantly greater α‐2,6 microglia sialylation (r = 0.522; p<0.0001) compared to plaque sialylation (r = 0.262) in the 5XFAD mouse model. Post‐mortem human AD cases displayed similar microglia sialylation patterns. Yet there was no significant correlation of between tau and α‐2,6 SA (r = ‐0.143; p<0.0001) in human AD compared to microglia sialylation (r = 0.279). Qualitatively, 5XFAD mice and human AD display similar recognition of Aβ plaque with O‐linked glycosylation patterns.

Conclusions

We observed significant α‐2,6 sialylation of microglia in 5XFAD mice and post‐mortem human AD which was independent of tau pathology. Additionally, intriguing patterns of O‐linked SA are present surrounding Aβ plaques using novel histological techniques. Next, we will closely investigate subsets of sialylated microglia to determine what forms of O‐linked SA may reduce clearance of debris by microglia while actively comparing Aβ plaque sialylation in human AD cases.
Corticobasal degeneration or hepatic encephalopathy, False positive and/or congruence between clinic and PET‐FDG imaging
Authors: Lacombe Guy , Provost Sylvain , Paquet Nancy , gosselin Sylvie , Pelletier Martin , Lariviere Mathias
Published: December 2023

Background

to put into perspective the relative clinical evidence meeting the criteria of corticobasal degeneration but modified by the treatment of a metabolic disease

Method

Multidisciplinary clinical follow‐up of a patient meeting the cognitive, speech and neurological criteria for a degenerative disease by documenting the evolution of both functional, cognitive and functional imaging during the treatment of hepatic encephalopathy

Result

Pt of 82 y/o presents with a deterioration over 6 months of a left extrapyramidal syndrome with dystonia of this hemibody, with a dysphasia‐dysphonia spastic and ataxic documented in speech therapy compatible with corticobasal degeneration. MRI shows mild leukoaraiosis, The FDG PET‐Scan is also compatible with corticobasal degeneration. EEG done for abnormal movements is suggestive of hepatic encephalopathy in the absence of laboratory abnormality except for a very slight increase in ammonia. Ultrasound suggests the onset of liver disease. After 6 months of treatment of encephalopathy there is a slight clinical improvement. After one year of treatment the patient becomes totally autonomous with complete regression of neurological signs, dysexecutive disorders and social cognition deficits and PET‐FDG has normalized. 36 months later he is totally autonomous and is back to works as a historical tour guide.

Conclusion

It is impossible for us after 36months of follow‐up to determine whether the metabolic disease has unmasked a degenerative disease early or has simulated it. We review some possible false positive situations on FDG PET‐Scan. DAT‐Scan will be done.
Glial and neuronal mechanisms contributing to differential risks in TREM2 R47H and R62H variants in Alzheimer’s Disease
Authors: Fancy Nurun N , Willumsen Nanet , Tsartsalis Stergios , Khozoie Combiz , Mcgarry Aisling , Muirhead Robert , Schneegans Eleonore , Davey Karen , Chau Vicky , Smith Amy , Thomas Michael , Scotton William J. , Hardy John A. , Huh Dann , Jackson Johanna , Matthews Paul M
Published: December 2023

Background

Coding variants in the microglial TREM2 ectodomain differentially (R47H> R62H) increase the risk of Alzheimer’s disease (AD). To define mechanisms responsible in glia and neurons, we aimed to characterise neuropathology and transcriptomic responses in heterozygotes for these TREM2 variant alleles and for common allele homozygotes (CV) in non‐diseased (n = 16) and AD (n = 42) brain cortical tissue from 58 donors.

Method

Using immunohistochemistry (IHC) and imaging mass cytometry (IMC), we characterised neocortical b‐amyloid and AT8/PHF1 pTau pathology with CV (n = 30) and the R47H (n = 11) or R62H (n = 17) TREM2 carriers. We performed single nuclear RNA sequencing to test for the differential gene expression (DGE) in TREM2 and CV cortical tissues with greater 4G8+ b‐amyloid‐ or PHF1+ pTau‐immunostaining.

Result

There was a two‐fold increase in 4G8+, a three‐fold reduction in AT8+ but no change in PHF1+ immunostaining with AD in both variants versus CV. We found a reduced expression of genes associated with TREM2 function in R47H carriers relative to CV however enhanced microglial activation in R62H carriers. This was associated with an up‐regulation of pathways such as ‘neuroinflammation signalling pathway’ in R62H not seen in R47H. CV astrocytes had little DGE with increasing pathology however both variants (R47H>R62H) had an increased proportion of differentially expressed genes suggestive of a heightened activation state. R47H and R62H astrocytes impacted pathways had opposing actions such as ‘synaptogenesis signalling pathway’ and ‘PDGF signalling’ pathways downregulated in R47H but upregulated in R62H. Neuronal gene expression changes were evident in all variants, however greatly enhanced in R47H in response to 4G8+ b‐amyloid. With increasing PHF1+ pTau gene expression changes were mainly seen in R47H. Excitatory and inhibitory neurons both exhibited DGE in R47H carriers and impacted pathways centred around those involved in ‘synaptogenesis signalling pathway’, ‘SNARE signalling pathway’ and ‘synaptic long term depression’.

Conclusion

This analysis identified novel disease‐associated transcriptomic differences in the glial response to TREM2 and the secondary neuronal responses that can explain differences in the genetic AD risk conferred by these two TREM2 risk variants.
Deciphering the Genomic Regulatory Architecture of iPSC Derived Oligodendrocytes from Diverse Ancestries for Alzheimer’s Disease Studies
Authors: Ramirez Aura M , Shepherd Jihanne J , Coombs Lauren , Simon Shaina A. , Moura Sofia , Rajabli Farid , DeRosa Brooke A. , Muniz Maria , Whitehead Patrice , Adams Larry D. , Mena Pedro R. , Illanes‐Manrique Maryenela Z , Starks Takiyah D. , Tejada Sergio J. , Byrd Goldie S. , Cornejo‐Olivas Mario , Feliciano‐Astacio Briseida E. , Rissman Robert A , Wang Liyong , Xu Wanying , Jin Fulai , Griswold Anthony J. , Young Juan I. , Dykxhoorn Derek M. , Vance Jeffery M.
Published: December 2023

Background

The effect of variants associated with Alzheimer’s disease (AD) can be influenced by ancestry, which determines the genomic regulatory architecture (GRA). A global understanding of GRA in the context of AD is imperative to interpret the variability associated with AD risk genes across populations. Most studies up to date have focused on studying GRA in European ancestry, in this study we aimed at determining the GRA in African, Amerindian, and European ancestries. Since GRA is cell specific, we developed a human induced pluripotent cells (hiPSC) based model for oligodendrocytes (OLs), a cell type which has limited studies focused on AD.

Method

Cells from AD patients or non‐cognitively impaired controls with >90% of either Amerindian, African or European global ancestry were differentiated using a modified multi‐stage protocol that promotes the development and enrichment of oligodendrocytes in neural spheroids. After terminal differentiation, cells were collected and lysed to isolate nuclei for Multiomic profiling of chromatin accessibility and transcriptome using Single Cell ATAC and Single Cell RNA‐seq. Additionally, we examined chromatin interactions using Hi‐C analyses.

Result

We identified oligodendrocyte lineage cells at different stages of development ranging from dividing cells with transcriptional profiles consistent with those of oligodendrocyte precursor cells (OPC) to mature myelinating oligodendrocytes. We compared the oligodendrocytes clusters across ancestries, cases versus controls and APOE genotypes to characterize the genomic landmarks and signatures associated with AD related GWAS loci. Astrocytes and neurons were also derived within our 3D spheroids, allowing us to study ancestry‐related cell type specific changes in GRA.

Conclusion

Our results provide ancestry‐specific insights into oligodendrocyte chromatin structure and gene regulation in the context of AD. These results offer an integrated view of the GRA of a previously overlooked cell lineage that constitute a large population in the central nervous system and is compromised during AD in terms of abundance and function. This will expand the available functional resources for gene identification studies in African American and Hispanic/Latino studies.
French Memory Support System: A Proof‐of‐Concept Study
Authors: Fievre Fadia Johanna , Sweet Lisa , Knoefel Frank , Santos Octavio A , Thomas Neil W.
Published: December 2023

Background

Mild cognitive impairment (MCI) confers a higher risk of developing dementia and may interfere with instrumental activities of daily living (IADLs). The Memory Support System (MSS) is a curriculum and calendar/note‐taking system that has proven effective to sustain independence in IADLs in individuals with MCI and protect mood among support partners. Until recently, the MSS has only been utilized among English‐ and Spanish‐speaking samples.

Method

This study investigated the use of a translated and culturally adapted MSS in four French‐speaking participants with MCI (75% female, age Mean = 69.3 [SD = 5.6], education M = 15 [SD = 2.6]) and their support partners. A within‐subject multiple baseline design (baseline, treatment end and 8‐week follow‐up) in a 10‐session, 2 to 3‐week MSS training schedule was utilized. Outcome measures included treatment adherence as well as self‐ and informant‐report questionnaires of IADLs, cognitively‐relevant everyday abilities, self‐efficacy, anxiety, depression, caregiver burden, and quality of life.

Result

By treatment end and follow‐up, participants with MCI showed improvement in adherence to the MSS calendar (Cohen’s d = ‐3.32 & ‐2.31); IADLs (d = 0.83 & 0.68); everyday abilities requiring memory (d = 0.35 & 0.43) and planning (d = 0.47 & 0.40); self‐efficacy (d = ‐1.43 & ‐1.62); symptoms of depression (d = 0.26 & 0.71) and anxiety (d = 0.09 & 0.2); and quality of life (d = ‐0.71 & ‐0.9). Support partners showed improvement in their own quality of life (d = ‐0.34 & ‐0.85) and depressive symptoms (d = 0.19 & 1.33), while their caregiver burden and anxiety symptoms generally remained unchanged.

Conclusion

Findings suggest that with appropriate training, French‐speaking participants with MCI can and will use the MSS. This may lead to improvement in their IADLs, some cognitively‐relevant everyday abilities, anxiety symptoms, and self‐efficacy. MSS training may also improve depressive symptoms and quality of life in both participants with MCI and their support partners. Overall, although results are generally consistent with previous studies using the MSS, further research using a larger sample of French speakers with MCI is needed to confirm current findings.
Developing Care Partner Activation Program among Filipino American Care Partners of Persons with Dementia
Authors: Ramos Mary Dioise
Published: December 2023

Background

Attention must be given to Filipino‐Americans since they are a growing underrepresented population and limited research exists on their healthcare needs, priorities, and research engagement. The broad goal of this project is to address the unique challenges related to the provision of Dementia care among Filipino‐Americans.

Method

Mixed‐method sequential, transformative design to develop and test a program for care partners to strengthen their abilities to manage care activities, emergency department visits, and hospital admissions who experience disparities in access to care.

Result

In partnership with different Filipino‐American community‐based organizations, leaders were identified to explore capabilities and resources available to initiate the care partner activation program. Major support needed in areas related to: family dynamics and caregiving experience, spiritual and cultural values, communication and understanding of the disease process, advocacy groups, socio‐emotional support, insurance system, and financial concerns.

Conclusion

Educational opportunities exists for Filipino‐American families and communities related to provision of care among patients with dementia. Community‐based participatory research need to be promoted to encourage families and patients to engage and improve healthcare utilization.
Elucidating Cell Diversity and Functions of Human Brain Borders in Alzheimer’s Disease
Authors: Kearns Nicola , Iatrou Artemis , Avey Denis , Yu Chunjiang , Philippe Tristan , Flood Daniel , De Tissera Sashini L , Mullaney Zachary , Xu Jishu , Gaiteri Chris , Bennett David A. A , Wang Yanling
Published: December 2023

Background

Emerging evidence shows that the brain border regions act as a functional neuro‐immune interface to conduct essential immune surveillance and immune defense1. The dysfunction of border immunity contributes to aging, microglial inflammatory response, and neurodegeneration2‐3.

Method

We conducted single nuclei multiome to simultaneously profile gene expression and open chromatin of dissected postmortem human brain borders from aged individuals with and without Alzheimer’s Disease (AD) (n = 32). We further generated border cell models from iPSCs and postmortem leptomeningeal cells to understand the effects of genetic and environmental factors on border cells.

Result

We detect diverse cell types at the brain borders, including unique endothelial, mural, immune, and fibroblast subtypes. Border‐associated macrophages (BAMs) display differential gene expressions from microglia and express AD risk genes, as nominated by genome‐wide association studies (GWAS). We discover cell‐type‐specific differentially expressed genes in AD individuals, particularly fibroblasts and BAMs. We identify gene regulatory networks and master regulators of specific border cell states. Human cell models of leptomeningeal cells display the signature of ex vivo AD fibroblasts upon amyloid‐β treatment, and iPSC‐derived choroid plexus models carrying the APOE4 risk alleles demonstrate differentially expressed genes related to immune and fibrotic response. Lastly, we explore ligand‐receptor interactions within the border niche and observe increased intercellular activities and altered communication patterns at AD brain borders.

Conclusion

Our study establishes a molecular map of human border cell types and reveals the functional effects of AD risk factors on brain border cells, providing significant insight into the border immune and fibrotic responses in AD pathogenesis.

References:

1. Alves de Lima, K., Rustenhoven, J. & Kipnis, J. Meningeal Immunity and Its Function in Maintenance of the Central Nervous System in Health and Disease. Annu. Rev. Immunol. 38, 597‐620 (2020).

2. Da Mesquita, S. et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185‐191 (2018).

3. Da Mesquita, S. et al. Meningeal lymphatics affect microglia responses and anti‐Aβ immunotherapy. Nature 593, 255‐260 (2021).
Posterior Primary Progressive Prosopagnosia: Imaging and Neuropathology
Authors: Appleton Johanna , Bradbury Kathleen , Shyer Madison , Finn Quentin , Arbones Victoria , Dickerson Brad C. , Cykowski Matthew D , Masdeu Joseph C. , Pascual Belen
Published: December 2023

Background

Prosopagnosia is common with right temporal lesions, often in the fusiform gyrus when caused by vascular pathology. When caused by frontotemporal dementia, the lesion typically begins in the temporal tip. We are reporting advanced imaging, including tau and inflammation, as well as neuropathology in a patient with pathology centered at the posterior extent of the fusiform gyrus.

Method

A 69‐year‐old man with apperceptive prosopagnosia and a negative amyloid positron emission tomogram (PET) underwent MRI and PET using 11C‐PBR28, an inflammation tracer, and 18F‐flortaucipir. V
T values for 11C‐PBR28 were calculated with the Logan plot and a metabolite‐corrected arterial input function. For 18F‐flortaucipir, the SUV ratio over the cerebellar gray matter was calculated for t = 80‐100 min. A neuropathological examination was conducted using standard procedures as well as phospho‐tau histochemistry.

Result

Atrophy and 18F‐flortaucipir uptake involved a similar region at the posterior extent of the right fusiform gyrus and, minimally, a symmetrical region of the left fusiform gyrus and an area in right premotor cortex. Involving the same regions, the 11C‐PBR28 signal was however more extensive than atrophy or 18F‐flortaucipir signal. At autopsy, the patient had corticobasal degeneration (CBD), with severe 4R tau involvement of temporo‐occipital, inferior parietal, and frontal cortices, as well as limbic regions and subcortical nuclei. The location of CBD pathology in this patient was highly atypical, as shown by comparing the neuropathological findings with the findings in two typical CBD patients.

Conclusion

Although prosopagnosia from ischemic and other lesions in the right posterior temporo‐occipital region is common, primary progressive prosopagnosia in the absence of amyloid has been described mostly with involvement of the right anterior temporal region. As exemplified by our patient, it can rarely happen with posterior temporal involvement and in this case the pathology was not TDP‐43 type C, as present in most patients with anterior temporal involvement, but corticobasal degeneration, a 4R tauopathy.
Mapping the effects of functional and structural network reorganization on the tau‐cognition relationship in Alzheimer’s disease
Authors: Ottoy Julie , Kang Min Su , de Wael Reinder Vos , Park Bo‐Yong , Bezgin Gleb , Lussier Firoza Z , Rahmouni Nesrine , Stevenson Jenna , Arias Jaime Fernandez , Soucy Jean‐Paul , Gauthier Serge , Bernhardt Boris , Black Sandra E. , Rosa‐Neto Pedro , Goubran Maged
Published: December 2023

Background

Tau pathology can spread through connectivity‐based networks, with certain regions (or epicenters) accumulating more tau than others. Such spatial vulnerabilities may be due to their unique apical position in the cortical hierarchy, which can be elucidated through ‘gradients of connectivity’ (Margulies 2016 PNAS). Prior work showed that the primary gradient of functional connectivity unveils a uni‐to‐transmodal topography of the healthy neocortex which highly correlates with a cognitive gradient of perception‐to‐abstraction. Here, we hypothesized that the gradients of functional/structural connectivity interact with tau to affect cognitive functions in Alzheimer’s disease (AD).

Method

We included 213 participants from TRIAD (103 CN Aβ‐, 103 CN Aβ+, and 75 CI Aβ+) with diffusion‐weighted MRI, resting‐state functional MRI, 18F‐MK6240 tau‐PET, and an extensive cognitive battery. We performed non‐linear dimensionality reduction on the individual functional and structural connectomes, and extracted the first components (‘gradients’) ‐explaining most variance (G1FC and G1SC). First, we compared G1FC_or_SC between diagnostic groups. Second, we investigated the interaction effect of G1FC_or_SC*tauSUVR on cognition (across 9 cognitive domains). Last, we investigated whether the tau‐cognition relationship changed in a topography‐specific manner along the cortical hierarchy, within (equally‐sized) gradient‐derived meta‐ROIs along G1FC_or_SC. Results were compared to Braak‐derived regional associations. Analyses were adjusted for age, sex, APOE, education, and multiple comparisons.

Result

We observed reduced segregation of functional networks in AD compared to controls, with unimodal (lower‐order cognitive) and transmodal (higher‐order cognitive) regions moving closer on G1FC. This may indicate loss of network specialization in AD. Participants who had both higher tau and G1FC alterations had more cognitive impairment (Fig.1A; shown for MMSE/language). This interaction‐effect was less pronounced with G1SC (Fig.1B). Last, tau correlated with cognition in a topography‐specific progressive manner (i.e., along the transmodal‐unimodal G1FC axis and anterior‐posterior G1SC axis) (Fig.1C). Notably, tau correlated with delayed memory progressively along the posterior‐anterior G1SC axis (R2 = 0.93 in all and R2 = 0.95 in A+) and BraakI‐VI axis (R2 = 0.77 in all and R2 = 0.28 in A+).

Conclusion

Our work supports the contribution of connectome‐driven tau distribution on cognitive impairment in AD. Connectome gradients may provide a spatial framework to study tau spreading along the major axes of brain organization underlying specific cognitive domains.
Blood pressure variability and functional network connectivity in older adults
Authors: Sible Isabel J , Jang Jung Yun , Blanken Anna E , Alitin John Paul M , Dutt Shubir , Marshall Anisa J , Kapoor Arunima , Shenasa Fatemah , Engstrom Allie , Gaubert Aimee , Nguyen Amy , Mather Mara , Nation Daniel A.
Published: December 2023

Background

Blood pressure variability is an emerging risk indicator for cerebrovascular disease and Alzheimer’s disease, independent of traditionally studied mean blood pressure levels. Recent studies suggest elevated blood pressure variability in older adults is also associated with attenuated cerebrovascular reactivity, which may have implications for functional hyperemia underpinning brain network connectivity. However, it remains unclear whether blood pressure variability is related to functional network connectivity. We examined relationships between beat‐to‐beat blood pressure variability in older adults and functional connectivity in multiple brain networks vulnerable to Alzheimer’s disease and related disorders (AD/ADRD).

Method

32 community‐dwelling older adults (mean [SD] age = 69.6 [7.5] years) without history of dementia or clinical stroke underwent continuous blood pressure monitoring during a 5‐minute period of rest and resting state fMRI. Blood pressure variability was calculated as variability independent of mean, an increasingly used index of variability uncorrelated with mean blood pressure levels. Functional connectivity was determined by resting state fMRI for several brain networks: default mode, salience, dorsal attention, fronto‐parietal, and language. Multiple linear regression examined relationships between blood pressure variability and functional network connectivity, controlling for age, sex, and mean blood pressure. Associations with mean blood pressure were also explored to directly compare potential effects with blood pressure variability.

Result

Elevated blood pressure variability was associated with lower functional connectivity in the default mode network (ß = ‐.55 [‐1.02, ‐.08]; p = .02). There were no significant associations between blood pressure variability and connectivity in other functional networks (p’s = .10 ‐ .62). Mean blood pressure was not related to functional connectivity in any network (p’s = .08 ‐ .98).

Conclusion

Older adults with elevated blood pressure variability exhibit resting state functional connectivity deficits in the default mode network. Findings add to literature supporting the role of blood pressure variability in neurovascular dysfunction and AD/ADRD. Blood pressure variability may represent an important but understudied early vascular risk factor for neurovascular dysfunction relevant to AD/ADRD, with potential therapeutic implications.
Analysis of brain functions in the older adults: A Systematic Review on functional near‐infrared spectroscopy
Authors: Kim Mi Kyeong , Lee Hamin , Yun Sohyeon , An Hyun Seo , Kim Inhye , Park Hae Yean
Published: December 2023

Background

As the aging phenomenon accelerates worldwide, cognitive health and improvement of the older adults are emerging as important issues. This study was conducted to obtain implications for future clinical and research directions related to elderly cognition by examining studies that identified the brain function of the elderly using brain activation or functional connectivity.

Method

Three databases(Web of Science, Scopus, Pubmed) were used to collect literature for a total of five years from January 2018 to December 2022. Using “(“older adult*” OR “elderly”) AND “fNIRS” AND (“functional activation” OR “functional connectivity”)” as the search term, we selected and analyzed the final 8 literature that matched the selection criteria and exclusion criteria of this study.

Result

There were 5 cases targeting healthy older adults and 3 cases for the older adults with mild cognitive impairment, and the most active study in China was shown. In addition, a total of six types of NIRS systems were used to explore brain function in the elderly, and five studies confirmed that the NIRS system produced in Japan was used. In the case of the number of channels used, it had a wide range of 14 to 48, and there were only two studies showing functional connectivity.

Conclusion

This study confirmed that it is possible to identify the cognitive function of the older adults using fNIRS, and at the same time, few studies have measured functional connectivity. Since brain regions do not work independently, it is essential to understand functional connectivity that identifies functional integration between brain regions that share similar functions, even if they are located apart. Therefore, based on the results of this study, it is believed that a better understanding of functional brain changes can be achieved if brain activation and functional connectivity are also identified when conducting cognitive‐related research in the elderly using fNIRS in the future.
Dementia Caregiver Burden associated with COVID‐19 quarantine: A South American Cohort Study
Authors: Arruabarrena Micaela Maria , Fernández Rodrigo S , Martinez Carlos , Corvalan Nicolas , Keller Greta , Sevlever Gustavo , Allegri Ricardo Francisco , Crivelli Lucía
Published: December 2023

Background

In December 2019, a new virus, Coronavirus disease (COVID‐19/SARS‐CoV‐2), burst into the world. Social distancing reduces its transmission and delays the spread peak. However, because of the late arrival of vaccines to our region, Argentina had a rigorous mandatory preventive social isolation (MPSI) policy that extended beyond global record. As a result, MPSI had a disruptive impact on the actions associated with the well‐being of dementia patients, and caregivers. In addition, MPSI added to the well‐known caregiver burden already present in many dementia patients’ caregivers. This study aims to investigate the impact of MPSI on dementia patients’ caregivers’ mental health and to identify predictors of caregivers’ burden.

Method

A sample of 112 caregivers (75.89% female; age 58.65 ± 14.30) of patients with dementia answered a survey with the following questionnaires: Zarit Burden Interview (ZBI), Weekly hourly load dedicated to dementia care, time spent on leisure activities (activity diary provided by Argentine National Institute of Statistics and Census), the Caregiver Activities Survey (CAS) and the Depression, Anxiety and Stress Scale (DASS‐21). These questionnaires evaluate caregiving characteristics and their impact on the caregiver. Additionally, history of COVID‐19 was recorded for patients, caregivers and people living with either of them.

Result

Most caregivers were women (75.89%). This difference hindered direct comparison between men and women. A regularized L2 regression was performed and the number of caregiving hours (β = 0.090), depression (β = 0.085), anxiety (β = 0.099), stress (β = 0.164), and fear of COVID‐19 (β = 0.141), were identified as predictors of caregiver burden. Finally, a mediation analysis was also performed, and hours of care (CAS; r = 0.254), being the primary caregiver, and fear of COVID‐19 (r = 0.335) were identified as mediators of the effect between anxiety, depression, stress (DASS) and burden (ZBI).

Conclusion

Caregivers of dementia patients show sequelaes of anxiety, stress, depression, and caregivers’ burden in the context of COVID‐19 spread and during MPSI. Being a primary caregiver, dedicating more hours to caregiving, and fear of COVID‐19 are factors that contribute significantly to caregiver burden and mediate between this burden and mood variables. Relief of caregivers' burden could be aided by the design of public health policies that specifically address the mediators identified in this study.
Race, inflammation, and amyloid deposition in Black/African American and Non‐Hispanic White older adults
Authors: Stradford Joy , Snitz Beth E. , Becker James T , Roush Rebecca E. , Reese Alexandria C. , Lopresti Brian J , Cisneros Geraldine , Potopenko Katey , Lopez Oscar L. , Cohen Ann D. , Pa Judy
Published: December 2023

Background

Black/African American (AA) older adults are twice as likely as Non‐Hispanic White (NHW) older adults to be diagnosed with Alzheimer’s Disease (AD) and related dementias. Inflammation and brain beta‐amyloid (Ab) may play a differential role in AD pathophysiology in AA and NHW older adults. We hypothesized that there would be racialized group differences in inflammation, amyloid deposition, and everyday discrimination.

Method

One hundred and ninety‐eight participants (Table 1) were recruited in Pittsburgh, PA and the surrounding areas as a part of the Human Connectome Project. Blood‐based biomarkers of inflammatory markers interleukin 6 (IL6) and tumor necrosis factor alpha (TNFa) were examined. Brain Ab was quantified using Pittsburgh Compound‐B (PiB) Positron Emission Tomography (PET) imaging standardized uptake value ratio (SUVr). Experiences of discrimination were measured on a subset of 66 participants (mean age = 62.62±9.37 years, 46.97% AA) using the Everyday Discrimination Scale (EDS). Analysis of covariance, controlling for age, were conducted to examine the racialized group differences for TNFa, IL6, Ab SUVr. Independent samples t‐tests were conducted to compare EDS by racialized group.

Result

Participants. AA participants were on average 6.58 years younger than NHW participants and more likely to have a clinical diagnosis of impaired without complaints, mild cognitive impairment (MCI), or AD (all p’s<.05) (Table 1). Additionally, in the subset of participants with EDS data, AA participants experienced higher total discrimination than NHW participants (p<.05).

Inflammation. NHW participants had higher TNFa inflammation levels than AA participants (p = .029). No differences by racialized group were observed for IL6.

PiB‐PET. The frequency of amyloid positivity was higher in NHW than AA participants (p = <.001). Global Ab SUVr was higher in NHW than AA participants (p<.05).

Conclusion

The results from this study provide evidence of higher peripheral blood inflammation and PiB PET binding in NHW than AA participants, but higher likelihood of clinical diagnoses and more experiences of discrimination in the AA than in NHW participants. Future investigation of these racialized differences as they relate to age and other determinants of health are needed.
Associations Between Cardiovascular Risk Factors and Arterial Spin Labelling Derived Perfusion Parameters
Authors: Tee Mervin , Padrela Beatriz E. , Konstandin Simon , Eickel Klaus , Günther Matthias , Petr Jan , Mutsaerts Henk‐Jan , Hilal Saima
Published: December 2023

Background

Decreased cerebral blood flow (CBF) and deterioration of blood‐brain barrier (BBB) are suggested to be precursor conditions of cognitive impairment. Using a novel multi‐echo‐time arterial spin labelling (ASL) protocol, we examined the time of exchange (Tex) of water across the BBB as a measurement of BBB permeability. We further examined the association of cardiovascular risk factors with Tex in an ongoing cohort study.

Method

Data (n = 29, mean age: 55.9±6.1years, 69% women) were drawn from Neurological biomarkers of Blood, MRI and Cognition (NEURO‐BMC) study performed at National University of Singapore. NEURO‐BMC is an ongoing prospective cohort study (age: 45‐65 years) on brain changes in a subclinical phase of cognitive impairment. A multi‐echo, Hadamard‐encoded multi‐post‐labelling‐delay pseudo‐continuous ASL (PCASL) protocol was used on a 3T scanner. ExploreASL was used with a modified version of FSL FABBER(4) to quantify cerebral blood flow (CBF), arterial transit time (ATT), and Tex. ASL‐extracted parameters were compared with cardiovascular risk parameters such as blood pressure (BP), BMI and smoking status.

Result

High systolic and diastolic BP were associated with significantly reduced Tex (Fig 1). Additionally, higher systolic and diastolic BP showed a trend of increased ATT and reduced CBF, though the associations were not statistically significant (Table 1). High BMI had a significant association with increased ATT and reduced CBF. However, no trend was observed between BMI and Tex. Participants who ever smoked were observed to have a reduced Tex and CBF and increased ATT, but statistical significance was only found for CBF (Fig 1).

Conclusion

In this pilot study, we showed that BBB‐ASL‐derived parameters ‐ ATT, CBF, and Tex ‐ were associated with BP, BMI, and smoking status. While the sample size for this preliminary analysis was too small to make a definitive conclusion as not all associations were statistically significant, all studied cardiovascular risk factors showed their potential in increasing the risk of BBB deterioration. Further investigation with a larger sample size and other health risk factors to assess these observations is warranted.
Dementia Research Policy and Infrastructure in Costa Rica as a Central American Upper‐Middle Income Country
Authors: Josephy‐Hernandez Sylvia E. , Pérez‐Rojas Randall , Acosta‐Egea Sabrina , Miranda‐Valverde Erick , Román Norbel , Steele Hector Anthony , Aguilar Daniel Valerio , Leon‐Salas Jorge M
Published: December 2023

Background

Clinical research in Costa Rica came to a halt in 2010 when the legislative assembly, due to concerns around lack of oversight, declared that no studies could continue until research involving human beings was regulated by law. Legislation did not come to pass until 2014. Currently, clinical research is performed within both the public and private healthcare systems. With this study, we aim to showcase the growth of research in dementia in Costa Rica since 2014 and explore gaps that remain.

Method

We performed a bibliographic search for dementia research in Costa Rica, both in English and in Spanish. Search engines included PubMed, PMC, and Google Scholar. We also collaborated with clinicians and researchers from private and public institutes to delineate the current research network.

Result

We extracted 60 publications; 90% of the articles were published after 2014, with the largest increase after 2019 (63% of publications). 60% of publications derived from international collaborations. We identified 89 Costa Rican researchers authoring these publications, with 82% of authors belonging to the public sector. Two main public universities (University of Costa Rica and National University) and two main public hospitals (National Geriatrics Hospital and San Juan de Dios Hospital) produced most of the data. Important international collaborations including LatAm Fingers are taking place with one private hospital (Clínica Bíblica Hospital). An aspirational international collaboration is the inclusion of Costa Rica in ReDLat.

Conclusion

There has been an exponential growth of research in dementia in Costa Rica since 2014, reflected in the highest growth of publications after 2019. Most publications have been enabled by international collaborations. Despite a significant lack of funding and infrastructure, most of the research is taking place within the public system. Increased funding within the public system, as well as public‐private collaborations, would allow for further research development.