bluuebunny/crossref_metadata_2025 huggingface dataset:
Social engagement, amyloid burden, and dementia: the Atherosclerosis Risk in Communities (ARIC)‐PET study
Authors: Groechel Renée C. , Liu Chelsea , Knopman David S. , Koton Silvia , Kucharska‐Newton Anna M. , Liu Albert C. , Lutsey Pamela L. , Mosley Thomas H. , Palta Priya , Sharrett Richey , Walker Keenan A. , Wong Dean F. , Gottesman Rebecca F.
Published: December 2023

Background

Although amyloid deposition in the brain is often associated with subsequent dementia risk, not everyone with brain amyloid will develop dementia. This discrepancy illustrates the potential importance that risk factors and lived experiences may have in modifying this association. Compared to participants with low social engagement (SE) in mid‐life, we hypothesized that participants with high mid‐life SE will show a weaker association between amyloid burden and incident dementia.

Method

We included data from 310 non‐demented participants of the Atherosclerosis Risk in Communities (ARIC)‐PET study. Social support and isolation were assessed via interviewer‐administered questionnaires (Visit 2; 1990 – 1992). Based upon categorization of both factors, participants were classified as having high, intermediate, or low mid‐life SE (Table 1). Brain amyloid was evaluated with florbetapir PET (Visit 5; 2011‐2014). Elevated amyloid burden was defined as standardized uptake value ratio (SUVR) >1.2 in the global cortex. Incident dementia cases were identified from visit 5 through 2019 through ongoing surveillance utilizing in‐person neurocognitive testing, informant interviews, and hospitalization codes. Relative contributions of mid‐life SE and elevated florbetapir SUVR to incident dementia, independently and with multiplicative interaction terms, were evaluated with Cox regression models, adjusted for demographics, APOEε4 and vascular risk factors

Result

Among 310 participants, 48 developed dementia (median follow‐up: 4.7 years). Mid‐life SE and elevated SUVR each independently predicted dementia risk but did not interact on a multiplicative scale. Participants with high or intermediate mid‐life SE, relative to low mid‐life SE, were less likely to develop dementia (Table 2). Although the interaction between mid‐life SE and elevated SUVR was not significant, stratified models suggested a stronger association between amyloid burden and dementia in participants with high mid‐life SE (Table 3).

Conclusion

Greater mid‐life SE was associated with lower odds of developing dementia, independent of elevated SUVR. Although protective, there was no strong evidence for effect modification of mid‐life SE on the association between amyloid and dementia risk. Future longitudinal studies evaluating the potential influence of social factors measured throughout the life course are needed to inform our understanding as to what factors may preserve cognition in the presence of elevated brain pathology.
The pTau interactome in sporadic Alzheimer’s disease across APOE genotypes
Authors: Thierry Manon , Ponce Jackeline , Ariza Mitchell Marta , Askenazi Manor , Faustin Arline , Leitner Dominique , Pires Geoffrey , Kanshin Evgeny , Drummond Eleanor , Ueberheide Beatrix , Wisniewski Thomas
Published: December 2023

Background

APOE polymorphism is the major genetic risk factor for sporadic Alzheimer’s disease (AD), characterized by the abnormal accumulation of β‐amyloid (Aβ) and phosphorylated Tau (pTau). Although the various ApoE isoforms are known mostly to differentially modulate Aβ aggregation and clearance, recent data support an influence of APOE genotype on pTau accumulation, which correlates better with AD symptom progression. The exact effects of ApoE isoforms on pTau metabolism, however, remain unclear.

Method

The localized proteomic methods developed in our laboratory, on post‐mortem human brain, are an ideal strategy to elucidate these aspects de novo. Co‐immunopurifications (IP) against pTau pSer396/pSer404 (PHF1) from frozen frontal cortex were combined with mass spectrometry to map out, for the first time, the pTau interactome across APOE genotypes in 10 sporadic AD cases (n = 5 APOEε3/ε3 and n = 5 APOEε4/ε4).

Result

A total of 1130 and 1330 proteins were enriched in the IPPHF1 samples of the APOEε3/ε3 and APOEε4/ε4 groups (FC ≥ 1.50, IPPHF1 vs. IPIgG ctrl) and represented respectively 62% and 70% of the proteins previously identified as bona fide pTau interactors, validating our approach (Drummond et al., 2020). We identified 184 and 176 proteins as bona fide pTau interactors in the APOEε3/ε3 and APOEε4/ε4 groups (SAINT scores ≥ 0.65). Only 79 pTau interactors were common to both APOE groups and were mostly involved in proteostasis pathways (ubiquitin‐proteasome system, RNA metabolism, endo‐lysosomal trafficking). The pTau interactome of the APOEε3/ε3 group contained 17 proteins upregulated in APOEε3/ε3 cases (FC ≥ 1.50, IPPHF1 (APOEε3/ε3) vs. IPPHF1 (APOEε4/ε4))), a large majority of which being involved in RNA binding, processing or splicing (13/17 proteins, STRING analysis). The pTau interactome of the APOEε4/ε4 group contained 33 proteins upregulated in APOEε4/ε4 cases (FC ≥ 1.50, IPPHF1 (APOEε4/ε4) vs. IPPHF1 (APOEε3/ε3))), most of them being involved in synaptic transmission pathways (16/33 proteins, STRING analysis).

Conclusion

Our proteomic data highlighted an influence of the APOE polymorphism on pTau metabolism. These results will be validated in the human brain using histological and biochemical methods, paving the way to the identification of new therapeutic targets for AD.
Acetylcholine Receptor Agonists Exerted Neuroprotection Against Doxorubicin‐Induced Chemobrain
Authors: Ongnok Benjamin , Prathumsap Nanthip , Chunchai Titikorn , Arunsak Busarin , Pantiya Patcharapong , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2023

Background

Although doxorubicin has been broadly used in treating a wide range of cancers, it frequently causes a serious neurological consequences referred to as chemobrain in cancer patients. Chemobrain shares several key pathological features with Alzheimer’s disease (AD) including neuroinflammation and Tau pathology. In addition to the inhibition of acetylcholinesterase, the activation of a7nicotinic and muscarinic acetylcholine receptors (a7nAChR and mAChR) using their agonists has been considered an effective therapeutic target against dementia. However, the benefit of intervention with nAChR and mAChR agonists in DOX‐induced chemobrain has never been investigated.

Method

Twenty‐five male Wistar rats were assigned to received either (0.9% NSS) or doxorubicin (3 mg/kg; 6 doses) via intraperitoneal injection. Then, doxorubicin‐treated rats were divided into 4 intervention groups to treat with either vehicle, an a7nAChR agonist (PNU‐282987; 3 mg/kg), a mAChR agonist (bethanechol; 12 mg/kg), or a combined treatment of PNU‐282987 and bethanechol via intraperitoneal injection as a concomitant treatment with doxorubicin for a period of 30 days. After completion of the treatment paradigm, cognitive function was evaluated using the novel object location task (NOLT). The hippocampal tissues were dissected to enable further investigation.

Result

Systemic administration of doxorubicin impaired long‐term cognitive function in rats as shown by a decreased preference index in the NOLT (Figure A). Furthermore, doxorubicin‐treated rats exhibited neuroinflammation in the hippocampus as demonstrated by an increase in TNF‐a protein expression (Figure B) and an alteration in microglial morphology to a pro‐inflammatory amoeboid‐liked phenotype (Figure C). Notably, injection of doxorubicin markedly reduced the phosphorylation of GSK3b at Ser9 (Figure D) and upregulated the phosphorylation of Tau at Thr181 (Figure E). Also, a decline in the dendritic spine density in the CA1 region was observed in doxorubicin‐treated rats compared with the controls (Figure F). Interestingly, all AChR agonists restored cognitive function in rats in a similar manner by attenuating neuroinflammation and Tau phosphorylation while preserving dendritic spine density (Figure A‐F).

Conclusion

Together, activation of AChRs by their agonists protected against the neuropathology of doxorubicin‐induced chemobrain, indicating their potential role as a novel strategy to prevent chemobrain in patients receiving chemotherapy.
Differential cognitive and functional performance in racial and ethnic groups when stratified by consensus diagnosis: Findings from the NACC dataset
Authors: Pilonieta Giovanna , Geldmacher David S.
Published: December 2023

Background

Recent studies comparing non‐Hispanic Whites (NHW) to non‐Hispanic Blacks (NHB) with cognitive impairment found differences in associations between neuropsychological performance and ratings of daily function. Evaluating differences in these relationships by race and ethnicity may be important to interpreting disparities in clinical research outcomes for people with Alzheimer’s disease and related disorders.

Method

We compared demographic and performance variables across consensus diagnostic groups (CN, impaired‐not‐MCI, MCI, or dementia) at baseline in NHB (N = 1,609; 15.62%), Hispanic (N = 706, 6.86%) and NHW (N = 7,984,77.52%) adults in the NACC cohort, using data from Version 3.0 of the UDS, collected at the 37 NIA‐ADRCs from March 2015 to June 2022 (alz.washington.edu). Spearman’s rank correlation examined the associations between CDR‐GS, MoCA, and FAS scores by race and ethnicity within consensus diagnostic groups.

Result

Among 10,299 participants, 5,964 (57.91%) were women, mean age at baseline was 69.34 (±9.80), and mean education was 16.02 (±2.81) years. Significant differences in gender proportions between race and ethnic groups were observed. NHB had a higher proportion of female participants (χ2 = 233.39 <.0001); and reported the lowest FAS scores (Z = 200.67, P < .001). Hispanic participants had completed fewer years of education (Z = 3999.92, p = <.0001); and reported higher depressive symptoms (Z = 39.81, p = <.0001). Significant correlations were observed between all assessments by race and ethnic groups. When stratified by consensus group, in the NHW and NHB subsamples, CDR and MoCA scores associations were significant except in the “Impaired not MCI” groups. In the Hispanic subsample, significant correlations were only observed in the dementia group. After adjusting for the effects of GDS scores, correlations retained significance except in the NHB MCI group. Significant correlations between CDR and FAS scores were observed except in the “Impaired not MCI” group in the Hispanic subsample. These associations were retained after controlling for depressive symptoms except in the Hispanic MCI group.

Conclusion

Associations between cognitive and functional performance measures varied by racial and ethnic group when stratified by consensus groups in the NACC dataset. Specific ethnic, racial and socio‐cultural factors, as well as implicit/explicit examiner bias that may drive differences in performance warrant further study.
World Alzheimer Report 2022 ‐ How strong are global health systems: Lessons learned and case studies from across the globe
Authors: Weidner Wendy S
Published: December 2023

Background

Each year Alzheimer’s Disease International (ADI) publishes a World Alzheimer Report, a comprehensive source of global health and socioeconomic information on dementia. The theme of ADI’s 2022 World Alzheimer Report was post‐diagnostic support ‐ aiming to provide a global perspective on treatment, care and support models, barriers to access and areas of best practice, and the role of policy in strengthening health systems.

Method

We conducted 3 global surveys; with people living with dementia in 41 countries, informal carers across 68 countries, and health & long‐term care professionals in 69 countries. 215 global experts contributed 119 expert essay and case studies. We also highlighted commentary and perspectives from people living with dementia and carers.

Result

Key themes include a lack of access to post‐diagnostic support which impacted well‐being and health outcomes of families and professionals. 45% of people with dementia in lower‐ and middle‐income countries (LMICs) and 37% in high‐income countries (HICs) said they had not been offered support after their diagnosis. 66% of people with dementia did not have a personalised care plan. 54% of informal carers and 37% of professionals reported being stressed often or all the time. Case studies indicated stigma remains a major barrier and that care pathways are not clear or integrated – and often not culturally appropriate to ensure proper access to treatment and care. Carers and professionals expressed the need for better education and training. There were also areas of best practice to share.

Conclusion

Health and long‐term care systems must be strengthened in order to provide treatment, care and support of people living with dementia and their carers. National dementia plans provide a framework, but don’t always guarantee access. Stigma must be challenged and person‐centred care that is culturally appropriate, gender inclusive, coordinated and accessible must become the norm. Support for carers must be prioritised and education and training must be improved and expanded. There are radical differences both between and within countries in education, acculturation, access to services, family responsibilities, and ability to mobilise resources. Understanding how these differences shape dementia care practice is crucial for developing appropriate dementia care policies.
The Availability and Use of Anti‐Dementia Drugs: An International Survey
Authors: Tang Eugene Yee Hing , Weidner Wendy S , Robinson Louise
Published: December 2023

Background

There is currently no cure for dementia and few medications to help with the symptoms of dementia. However, there are acetylcholinesterase inhibitors, such as Donepezil, Rivastigmine and Galantamine, which are available to people with dementia but there is potential for inequality in their availability globally. A potential reason for this is that there is no anti dementia medication included in the World Health Organisation’s Essential Medicine List which potentially creates inequalities of access to evidence based care.

Method

In collaboration with Alzheimer’s Disease International, a global electronic survey was sent to explore the international use of cholinesterase inhibitors. Here we focus on donepezil as the most commonly prescribed first line anti‐dementia medication

Result

In total we received 73 responses from 39 different countries with all continents represented. Respondents included psychiatrists (n = 21), neurologists (n = 18), physicians (n = 8), geriatricians (n = 7), nurses (n = 4), general practitioners (n = 2), a psychologist (n = 1) and a pharmacist (n = 1). Respondents from all levels of income were included. The majority of participants (n = 66, 90.4%) did prescribe anti‐dementia medications and for the majority of these respondents (n = 50, 68.5%), Donepezil was the first line anti‐dementia medication. Nearly half of all participants (n = 31, 42.5%) reported that they would prescribe anti‐psychotic medication for dementia if they could not access anti‐dementia medication. The efficacy of anti‐dementia drugs was mainly determined by family or carer reports (n = 64, 87.7%) followed by cognitive assessment (n = 54, 74%) and then the patient’s subjective account (n = 50, 68.5%). Participants when asked about their criteria for stopping anti‐dementia medications mainly reported that it was side/adverse effects and how globally/holistically effective the medication was rather than cognitive assessment alone.

Conclusion

There are concerns that without access to commonly prescribed anti‐dementia drugs, this may introduce harms to people with dementia as they could be prescribed antipsychotics instead. Emphasis should be given to find ways for all people living with dementia, regardless of geographic or socioeconomic status, to access effective and safe anti‐dementia drugs such as donepezil.
Association between lipopolysaccharide, immune biomarkers and cerebral amyloid‐beta deposition in older adults with mild cognitive impairment & major depressive disorder
Authors: Feng Vivian , Lanctôt Krista L. , Herrmann Nathan , Kiss Alex , Fischer Corinne E. , Flint Alastair , Mah Linda , Mulsant Benoit H. , Pollock Bruce G. , Rajji Tarek K. , Tumati Shankar , Verhoeff Nicolaas Paul L.G. , Graff‐Guerrero Ariel , Gallagher Damien
Published: December 2023

Background

Inflammatory activation and increased immune response to lipopolysaccharide (LPS, a cell wall component of gut bacteria) is observed in both depression and cognitive decline. Depression is associated with accelerated cognitive decline, and persistent inflammatory activation may link depression and cognitive decline in later life. We determined if LPS is associated with inflammatory activation and cerebral deposition of amyloid‐beta (Abeta) in older adults with Mild Cognitive Impairment (MCI) and/or remitted Major Depressive Disorder (rMDD).

Method

Serum samples of LPS, LPS‐binding protein (LBP, which enhances the inflammatory response to LPS), and inflammatory markers (Interleukin 6 [Il‐6], C‐reactive protein [CRP], Monocyte Chemoattractant Protein 1 [MCP‐1]) were measured using ELISA. Abeta deposition was measured using PET neuroimaging using [11C]‐PIB radiotracer. Global amyloid burden was calculated using a composite Standardized Uptake Value Ratio (SUVR) score with the cerebellar cortex as the reference region. Multivariable linear regression analyses, adjusting for significant demographic and genetic variables, were conducted to determine if LPS, LBP, inflammatory biomarkers, MCI and rMDD were independently associated with global cerebral deposition of Abeta.

Result

Among 155 study participants (79 with MCI only, 54 with both MCI and rMDD, 22 with rMDD only) we found a median Abeta SUVR of 1.41 (IQR 0.57). There was no significant association between LPS (beta ‐1.28, 95% CI ‐11.69, 9.13, p = 0.8) or LBP (beta ‐0.02, 95% CI ‐0.05, 0.006, p = 0.12) and global deposition of Abeta, following adjustment for age, sex, and APOE genotype. LBP was positively correlated with inflammatory biomarkers: CRP (r = 0.49, p < 0.001) and IL‐6 (r = 0.21, p = 0.01) but no inflammatory biomarker was significantly associated with Abeta deposition. Having a history of rMDD (beta ‐0.09, 95% CI ‐0.26, 0.08, p = 0.28) or MCI alone (beta ‐0.11, 95% CI ‐0.47, 0.049, p = 0.11) was not associated with deposition of Abeta.

Conclusion

In this cross‐sectional analysis, we did not find an association between LPS/LBP, immune biomarkers, remitted MDD and global deposition of Abeta. Future analyses should examine the longitudinal relationships between peripheral and central biomarkers of immune activation with cerebral Abeta deposition in patients and controls.
MRI of Neuroinflammation Using a Folate Receptor β‐Targeted Nanoparticle Contrast Agent
Authors: Badachhape Andrew A , Parekh Parag A , Bhandari Prajwal , Menon Renuka , Bhavane Rohan , Srivastava Mayank , Tanifum Eric , Annapragada Ananth , Ghaghada Ketan
Published: December 2023

Background

Neuroinflammation plays an important role in Alzheimer’s disease (AD) pathogenesis and disease progression leading to cognitive decline. Current efforts for non‐invasive imaging of neuroinflammation are based on using PET radiotracers. An MRI‐based contrast agent for imaging of neuroinflammation would be highly desirable due to widespread use of MRI in imaging of neurological disorders. Folate receptor β, a marker of pro‐inflammatory phenotype, is expressed in microglia. In this work, we investigated a folate‐targeted liposomal‐Gd contrast agent for molecular MRI of neuroinflammation in mouse models of AD.

Method

In vivo studies were performed in APP/PSEN1 mice, a model of amyloid pathology, and P301S mice, a model of tau pathology. Transgenic mice and wild‐type (WT) littermates (n = 6/genotype, 24 total) underwent pre‐contrast MRI using T1‐weighted spin echo sequences with 160 µm in‐plane resolution and 1.2 mm slice thickness. Delayed MRI was performed 4 days after systemic administration of a high T1 relaxivity liposomal‐Gd contrast agent bearing folic acid molecules. Animals were euthanized after the final imaging session for microscopic analysis of brain. Signal changes between pre‐contrast and post‐contrast MRI were determined in target regions of the brain.

Result

Transgenic APP/PSEN1 and P301S mice demonstrated signal enhancement in post‐contrast T1w‐MRI compared to pre‐contrast MRI. In comparison, WT control mice did not show signal enhancement in post‐contrast MRI. APP/PSEN1 transgenic mice exhibited greater relative enhancement (+5.9%, p<0.005) and lower inter‐subject variance than P301S mice (3.9%, p<0.05). Immunofluorescence analysis demonstrated higher burden of activated microglia in brains of transgenic mice compared to WT control mice.

Conclusion

A folate receptor β‐targeted liposomal‐Gd contrast agent enables in vivo MRI of neuroinflammation in mouse models of Alzheimer’s disease. Such imaging agents could play an important role in monitoring of Alzheimer’s disease progression leading to cognitive decline and evaluation of therapies that target neuroinflammation.
Multilayer network analysis of Alzheimer disease links multiscale paths to the phenotype
Authors: Lara‐Simon Elena , Garcia‐Ojalvo Jordi , Villoslada Pablo
Published: December 2023

Background

Alzheimer Disease (AD) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to behavior. However, how these scales, the endotype, interact with one another to define the clinical phenotype remains poorly understood.

Methods

Here we conducted a systems biology study of AD, based on multilayer network analysis and deep phenotyping that integrates genomics, CSF biomarkers, tau and amyloid‐beta PET, brain MRI, risk factors and clinical data, obtained from the ADNI collaboration. Multilayer networks were constructed using mutual information, a nonlinear measure of correlation, at each layer and between layers. Boolean simulations identified paths within and among all layers through which dynamic information is transmitted. Multiple linear regression was then used to predict the phenotype (clinical or imaging variables) from paths within the genetic, molecular and imaging layers.

Results

the most prominent paths that significantly predicted the phenotype included hippocampus atrophy and tau levels from CSF and PET. Our results thus show that integrating the flow of information across biological scales reveals relevant paths for AD.

Conclusion

paths identified by multilayer networks can be pursued as biomarkers or new therapeutic targets.
Cognitive rehabilitation protocol for people with Parkinson’s disease and cognitive symptoms
Authors: Alves Larissa Scoralich , Shigaeff Nadia ,   Interdisciplinary Group for Research in Neuropsychology and Gerontology
Published: December 2023

Background

Parkinson’s disease is the second most common neurodegenerative disease and affects the lives of people around the world. Approximately 30% to 40% of people with Parkinson’s disease also develop cognitive symptoms. Most notably impairments are observed in executive function, visuospatial abilities and memory are observed. An effective alternative to treat these symptoms is cognitive rehabilitation, but there are still too few publications presenting cognitive rehabilitation protocols for this population. The aim of the present study was to develop a rehabilitation protocol focused on cognitive symptoms in people with Parkinson’s disease.

Methods

A free search was conducted for publications on the topic of cognitive rehabilitation for people with Parkinson’s disease and cognitive symptoms. From the reading of these studies, a set of exercises aimed at training executive functions, visuospatial skills and memory was then developed.

Result

The elaborated protocol includes nine sessions of 60 minutes each. It should be used by appropriately trained healthcare professionals. The protocol consists of activities using paper and pencil, as essential materials, which means low application costs. The protocol includes activities aimed at training visuospatial skills (Figure 1), memory (Figure 2) and executive functions (working memory, reasoning, mental flexibility, problem solving and planning) (Figure 3) with an increasing level of difficulty.

Conclusion

This study presents the formulation and scientific dissemination of a protocol that is easy to use, inexpensive and effective in the rehabilitation of these individuals.

References: Aarsland, D., Batzu, L., Halliday, G. M., Geurtsen, G. J., Ballard, C., Ray Chaudhuri, K., & Weintraub, D. (2021). Parkinson disease‐associated cognitive impairment. Nature Reviews. Disease Primers, 7(1), 47. https://doi.org/10.1038/s41572‐021‐00280‐3

Balestrino, R., & Schapira, A. H. V. (2020). Parkinson disease. European Journal of Neurology, 27(1), 27‐42. https://doi.org/10.1111/ene.14108
Hemodynamic Response Biomarkers for Aging Brain Health: Bogalusa Heart Study
Authors: Chuang Kai‐Cheng , Ramakrishnapillai Sreekrishna , Madden Kaitlyn , Amant Julia St , McKlveen Kevin , Gwizdala Kathryn L. , Dhullipudi Ramasudhakar , Bazzano Lydia , Carmichael Owen T.
Published: December 2023

Background

In functional magnetic resonance imaging (fMRI), a hemodynamic response function describes how neuron firing events are translated into a blood oxygenation response that is detected through imaging. The HRF varies between individuals and between brain regions, and its characteristics are believed to be valuable biomarkers of neurovascular aspects of brain health. However, the impact of cardiovascular risks on HRF characteristics among diverse cognitively healthy middle aged and older adults is not well studied.

Method

137 Bogalusa Heart Study participants performed a Stroop task during fMRI (Table.1). The HRFs of each participant within eight regions of interest (ROIs) previously identified as activated by this task [1] were calculated using a deep learning method. Each HRF was characterized by four main parameters (Figure 1): time to peak (TTP), peak magnitude (PM), trough magnitude (TM), and area under the HRF curve (AUHRF). Linear regression models related HRF parameters to demographic, cardiometabolic, and cognitive measures.

Result

Table 2 shows the associations between demographic, cardiometabolic, and cognitive measures and HRF parameters. Younger age was associated with lower AUHRF in the inferior frontal gyrus (p‐value = 0.052). Whites (compared to African Americans) had lower PM in the angular gyrus and lower AUHRF in the anterior insula (maximum p‐value = 0.022). Better systolic blood pressure and diastolic blood pressure were associated with shorter TTP in the angular gyrus and cerebellum (maximum p‐value = 0.029). APOE 3‐3 genotype and better BMI were associated with shorter TTP in the middle frontal gyrus and fusiform gyrus (maximum p‐value = 0.025). Better white matter hyperintensity volume was associated with lower PM and TM in the anterior insula and cerebellum (maximum p‐value = 0.032). Better digit span backwards score, digit coding score, vocabulary score, and word reading score were associated with shorter TTP and lower AUHRF in the angular gyrus, middle frontal gyrus, and/or inferior frontal gyrus (maximum p‐value = 0.038).

Conclusion

In a diverse, cognitively healthy, middle‐aged community sample, HRF parameters tracked closely with recognized indicators of brain health. Overall, lower TTP, PM, TM, and AUHRF represent better brain health, as there is no delay and alteration in neural‐vascular coupling unit. References: [1] Sheu, L. K. et al. (2012). Psychophysiology.
Age‐ and sex‐dependent differences in cognitive decline in rat models of Alzheimer’s disease
Authors: Myers Sarah J , Roseborough Austyn D , Allman Brian L , Whitehead Shawn N
Published: December 2023

Background

Memory loss has been a central focus of Alzheimer’s disease (AD) research but executive dysfunction may be one of the earliest indicators of AD (Baudic et al., 2006). Executive function refers to a group of cognitive processes that are required for goal directed behaviours, such as working memory and cognitive flexibility. Amyloid‐β (Aβ) plaques and neurofibrillary tangles are considered the pathological hallmarks of AD, but evidence suggests that these are not the earliest pathologies to appear in the AD brain (Sperling et al., 2011). This highlights the importance of assessing both the prodromal and more advanced phases of AD in preclinical modelling. This study aimed to characterize age‐ and sex‐related changes in executive function, learning, and memory across normal aging in rats as well as in two aging transgenic rat strains of AD: TgAPP21 (Aβ plaque‐negative) and TgAPP/PS1 (Aβ plaque‐positive).

Method

Male and female wildtype Fischer 344, TgAPP21, and TgAPP/PS1 rats were used in this study. The TgAPP21 rat overexpresses the mutant human amyloid precursor protein but does not spontaneously develop Aβ plaques, serving as an important model of prodromal AD. The TgAPP/PS1 rat overexpresses mutant human forms of both the amyloid precursor protein and Presenilin‐1 and does develop age‐dependent Aβ plaques. These strains allowed us to assess cognition under three conditions (i) normal aging, (ii) increased Aβ without plaque deposition, and (iii) age‐dependent Aβ plaque deposition. At 3, 9, or 15 months of age the rats were tested for spatial learning and memory, working memory, and cognitive flexibility using the Morris water maze, the 8‐arm radial water maze, and a T‐maze set‐shifting task.

Result

Age‐dependent cognitive decline was observed across all genotypes but was exacerbated in both transgenic models. Effects of age, sex, and genotype varied across the cognitive tasks, emphasizing the importance of assessing multiple cognitive domains.

Conclusion

These findings expand our understanding of the roles of sex, age and Aβ plaque‐positive/negative environments in cognitive decline in preclinical rat strains of AD. Overall, this work supports further investigation into the pathologies driving these cognitive changes and potential biomarkers for earlier detection.
Clinical Factors Associated with Cognitive Impairment and Dementia Among Patients Experiencing Homelessness
Authors: Dobbins Sarah K , Chodos Anna H
Published: December 2023

Background

The population of people experiencing homelessness (PEH) is aging; Half of PEH are now 50 years old or older. Cognitive impairment among PEH is thought to occur earlier, at higher prevalence, and progress faster than in the general population. Homelessness and associated marginalized conditions pose substantial barriers to care of people with cognitive impairment or dementia.

Method

We examined the prevalence of cognitive impairment, dementia, and clinical factors associated with these diagnoses among PEH seen between 7/1/2019‐5/31/2022 in a San Francisco safety net clinic. Medical record data for those who accessed services targeting homeless adults was retained for analysis. We analyzed the data using chi‐squared, T‐tests, and adjusted regression on select variables.

Result

Among 8,387 adults who experienced homelessness, 326 (3.9%) had a diagnosis indicating cognitive impairment or dementia. Of these, the majority (303, 92.9%) had non‐specific diagnoses, such as “cognitive impairment” (207, 2.5%), problems with “cognitive function” (19, 0.2%), or “memory issues” (77, 0.9%). 114 had specific diagnoses such as dementia (74, 0.9%), Alzheimer’s (6, 0.1%), or neurocognitive disorder (34, 0.4%). Some diagnoses overlapped (e.g. “cognitive impairment” and “dementia” were coded for one patient.) More of those with dementia or cognitive impairment had HIV, diabetes, hypertension, depression and/or anxiety, alcohol‐use disorder, and prior TBI. Those with dementia/cognitive impairment were more likely to be male and older (Table 1). More of those with dementia/cognitive impairment were white, Black, or Asian/Pacific Islander, and fewer were Latinx. Since their last clinical encounter, more of those with dementia/cognitive impairment died. In adjusted regression, the difference in hypertension, depression/anxiety, alcohol use disorder, TBI, gender, and mortality remained significant (p<0.05).

Conclusion

Prevalence of dementia and cognitive impairment in this patient cohort is lower than has been previously estimated in PEH (4% vs up to 25%). Non‐specific diagnoses were more commonly recorded, suggesting under‐identification and under‐diagnosis in non‐research conditions. Those with dementia or cognitive impairment diagnoses had more chronic disease and psychiatric illness, and higher mortality than those without any diagnosis. Better identification of those with cognitive impairment and dementia among PEH can help define areas of focus in the care of these marginalized individuals.
Dysregulation of UFMylation pathway in Alzheimer’s disease
Authors: Yan Tingxiang , Heckman Michael G. , Murray Melissa E. , Dickson Dennis W. , Springer Wolfdieter , Fiesel Fabienne C
Published: December 2023

Background

Neuropathologically, Alzheimer’s disease (AD) is characterized by the presence of senile plaques composed of beta‐amyloid (Aβ) and neurofibrillary tangles made of hyperphosphorylated tau. Aβ and p‐tau have been shown to impact endoplasmic reticulum homeostasis, DNA damage response and autophagic functions. Intriguingly, alterations in these systems have also been connected to dysfunctions in UFMylation, a ubiquitin‐like posttranslational modification. Analogous to ubiquitin, UFM1, is conjugated to substrates via a catalytic cascade involving UFM1‐specific set of E1 (UBA5), E2 (UFC1), and a complex that consists of E3 ligase (UFL1), DDRGK1 and CDK5RAP3. UFMylation is reversible, and this is mediated by UFSP2. The UFMylation pathway is essential for brain development as complete loss of function of any of its components result in severe neurodevelopmental disorders. However, alterations in UFMylation and their role in and significance for age‐related AD remains unknown.

Method

We performed Western blot and Meso Scale Discovery based ELISA to measure the protein level of UFM1, UFSP2, tau, p‐tau and other UFMylation pathway components in human post‐mortem brain. Analyses were performed with RIPA‐ and 2% SDS‐soluble fraction from frontal cortex. To validate our finding in human tissues, we knocked out UFM1 and UFSP2 in ReN cells, a neural progenitor cell model that has already been used to study AD and that can be terminally differentiated in neurons.

Result

We found a significant reduction of RIPA UFSP2, but an increase of RIPA and SDS UFM1 in AD compared to controls. Strikingly, RIPA UFSP2 had a strong negative correlation with both RIPA and SDS UFM1. Furthermore. UFM1 was significantly increased in UFSP2‐KO neurons compared to WT, mirroring the negative correlation between UFM1 and UFSP2 observed in human brain. In addition, RIPA and SDS UFM1 had a strong positive correlation with p‐tau, indicating that dysfunctional UFMylation might play an important role for disease pathogenesis.

Conclusion

Reduction of RIPA soluble UFSP2 in human AD frontal cortex might result in the abnormal accumulation of UFM1 and this might further facilitate the AD pathogenesis. Because of its role for several central AD‐relevant pathways, the UFMylation pathway might be a potential therapeutic target for AD.
Improvisation while Aging
Authors: Hainselin Mathieu , Krueger Kristin R , Ben‐David Boaz , Keisari Shoshi
Published: December 2023

Background

Artistic interventions have potential to fundamentally improve the cognitive, emotional, and social functioning of older adults. Improvisation is based on spontaneous interaction, where individuals co‐create and interact without pre‐planning. While improvisation in cognitive and mental health interventions has become more popular, there is no review to synthesize its impact on older adults.

Methods

We reviewed the literature and summarized the effects of improvisation on the cognitive, emotional, and social well‐being of older adults.

Results

There is now a substantial body of literature on the emotional and cognitive benefits for adults without dementia. Community‐dwelling older adults (N = 78) that participated in 12 weeks of improv combined with life review techniques demonstrated a decrease in depressive symptoms, and an increase in well‐being and meaning in life (Keisari, Palgi,et al., 2022). Older adults who participated in a 9‐min mirror‐game exercise (N = 34) had improved attentional functioning and positive affect compared to those who attended a physical activity class (Keisari, Feniger‐Schaal, et al., 2022). Two single‐group studies with older adults (N = 15, 45) showed that participation in improvisation yielded significant improvements in social isolation and perceived stress (Lindquist et al., 2021), sense of spontaneity, flow, playfulness (Bassis et al., 2022). One qualitative study suggested that the participants experienced more attentiveness, relaxation, and increased stimulation and communication following improvisation practice (Lindquist et al., 2021). Other qualitative studies showed that improvisation can help build community, increase positivity, sense of comfort and ease with the unexpected, a sense of self‐development and self‐awareness (Morse et al., 2018; Yamamoto, 2020).

There is also growing evidence that older adults with dementia benefit from improv interventions. Older adults participating in improvisation interventions have experienced a reduction in depressive symptoms and increase in positive affect (N = 178; Zeisel et al., 2018). One qualitative study showed that improvisation with older adults with early stage dementia have therapeutic benefits such as improvements in learning, sociability, communication and self‐esteem (Stevens, 2012).

Conclusion

There is sufficient evidence that improv as an approach to improve the

cognitive, emotional, and social well‐being of older adults has strong potential and warrants further study.
Sleep disturbance associated with temporal lobe degeneration in frontotemporal dementia
Authors: Larsen Eva , Jiang Jessica , Monica Ciro Della , Hassanin Hana , Atzori Giuseppe , Dijk Derk‐Jan , Revell Victoria Louise , Eriksson Sofia , Warren Jason D
Published: December 2023

Background

Sleep abnormalities are increasingly recognized as markers and potential drivers of neurodegenerative proteinopathies. However, the sleep phenotype of less common dementias remains poorly characterised. In particular, clinical experience suggests that patients with focal temporal lobe degeneration in the frontotemporal dementia spectrum can experience sometimes striking sleep disruption. We recently had the opportunity to corroborate this clinical impression in a small series of representative patients participating in a larger cohort study.

Methods

To date, we have studied seven patients and three healthy age‐matched controls. The patients’ diagnoses comprise behavioural variant frontotemporal dementia associated with focal right temporal lobe atrophy (n = 3), semantic dementia associated with focal left temporal lobe atrophy (n = 2), young onset Alzheimer’s disease and logopenic aphasia (each n = 1). No participant had a past history of a clinical sleep disorder. Detailed data on sleep patterns, adapted standard sleep questionnaires (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale), overnight oximetry and neuropsychological test scores (covering domains of executive function, emotion processing, memory, and auditory perceptual learning) pre‐/post‐overnight sleep were collected with the assistance of patients’ caregivers.

Results

Two patients with right temporal lobe atrophy and one with left temporal lobe atrophy had marked sleep fragmentation, in one right temporal case accompanied by frequent sleep attacks, with increased overall time in bed and/or attempting to sleep. Epworth and Pittsburgh indices in these patients indicated significant daytime sleepiness and reduced sleep quality; none had evidence of significant sleep apnoea on overnight oximetry. Comparatively mild clinical sleep disturbances were reported in patients with other dementia diagnoses. However, there was evidence for reduced auditory perceptual learning benefit from overnight sleep relative to healthy older controls, particularly in the patients with underlying Alzheimer pathology.

Conclusions

These preliminary findings suggest that focal temporal lobe degeneration may be associated with clinically relevant sleep disruption, as part of the more pervasive derangement of homeostasis in these syndromes. Further work is indicated to define the hypnic phenotype in detail, with sleep electrophysiology and correlative behavioural, neuroimaging and laboratory data in larger patient cohorts.
Impact of COVID‐19 in cognitively unimpaired individuals and dementia caregivers from the Peruvian Alzheimer Disease Initiative (PeADI)
Authors: Illanes‐Manrique Maryenela , Mena Pedro R. , Cubas‐Montecino Diana , Adams Larry D. , Sarapura‐Castro Elison , Castro‐Suarez Sheila , Rios‐Pinto Julia , Mejía Koni K. , Medina‐Colque Angel , Beecham Gary W. , Cornejo‐Herrera Ivan , Vance Jeffery M. , Ochoa‐Valle Edward , Cuccaro Michael L. , Cornejo‐Olivas Mario , Pericak‐Vance Margaret A.
Published: December 2023

Background

The COVID‐19 pandemic has profoundly affected people’s lives worldwide. Stress and social restriction have a negative physical and psychological effect on people with dementia and their caregivers. Peru was one of the countries that experienced social restrictions and high rates of COVID‐19 morbidity and mortality.

Methods

We assessed the NIA‐NIH COVID‐19 impact survey for unrelated cognitively unimpaired (CU) individuals and caregivers from the PeADI cohort (case‐control genetic study for Alzheimer’s disease and related dementias) from five different regions across Peru.

Results

We analyzed 249 COVID‐19 impact surveys,65 dementia patient caregivers and 184 older CU individuals. Among caregivers,86% felt isolated and 55.3% less connected with friends and family. 87.6% felt disrupted in everyday life, and 83% could not control the important things in their life. 44.6% found more difficult to provide care. The limitations on care include:physician appointments 64.6%,respite by family or friends 36.9%,day activity programs 32.35%, and overnight or extended‐stay respite care 16.9%. About 61.5% of them significantly reduced their household income. Almost 51% negatively changed their willingness to participate in clinical research if it required in‐person visits. Among the 184 CU individuals (mean age: 69.5± 3.8 years; 58.2% women). About 40.2% had new or worsening symptoms while thinking they had COVID‐19.About 60% were tested for Covid‐19 at least once, 29.3% were diagnosed with COVID‐19, and 2.1% were hospitalized. About 70% felt worried about getting or being reinfected by COVID‐19, 68.5% felt isolated from family and friends, 84.2% felt disrupted daily life, and 68.4% felt unable to control the important things in their life. About 60% had significantly reduced household income.About 52% of the CU noticed health changes (memory and thinking 31.2%, depression 42.7%, anxiety 51%, or behavior 46.8%).About 58% changed their willingness to participate in clinical research if it required in‐person visits.

Conclusions

Our results suggest that the COVID‐19 pandemic has affected dementia patient caregivers and CU individuals, both experienced variable changes in their mental health and significantly reduced household income.Caregivers have significant concerns regarding limited access to healthcare for their patients.CU individuals experienced fear of COVID‐19 reinfection.Further longitudinal surveys are required to explore changes in neuropsychiatric symptoms over time.
ABCA7 Mutations Can Present as Behavioral Variant Frontotemporal Dementia Without Amyloid Pathology
Authors: Snyder Allison , Shatz Rhonna
Published: December 2023

Background

ABCA7 was identified as an Alzheimer’s disease (AD) risk gene in 2011 through GWAS studies and subsequently its role in pathogenesis was confirmed via in‐vivo studies demonstrating loss of ABCA7 was sufficient to the trigger amyloid cascade. The most common presentation of ABCA7 loss of function mutations is an amnestic syndrome, however it less commonly can present with behavioral or motor symptoms. While the described clinical presentation can vary, almost all cases have been associated with AD pathology. Here we present three cases of bvFTD clinical syndromes in ABCA7 mutations carriers without evidence of AD pathology.

Method

Patients underwent a comprehensive clinical assessment including neurological history, examination, neuropsychological testing, MR brain imaging, and lumbar puncture. AD biomarkers were assessed through CSF testing. Genetic testing was obtained through CLIA certified whole genome sequencing.

Result

We identified three individuals with mutations in ABCA7. Two of these individuals harbor the p.I1878M mutation and one with the p.W1214* mutation on genetic testing. They presented with behavioral variant frontotemporal dementia with no evidence of amyloid pathology on CSF biomarker testing.

Conclusion

We present three cases of symptomatic ABCA7 mutation carriers without evidence of underlying AD pathology. The exact function of ABCA7 is unknown, however its purported involvement in lipid transport and immune responses are common pathways in neurodegenerative disease and raises the possibility of converging disease cascades.
The Performance of Memory Scales for Predicting Alzheimer’s Disease Biomarkers in Amnestic Mild Cognitive Impairment Patients
Authors: Sarutikriangkri Yuthachai , Hiransuthikul Akarin , Booncharoen Kittithatch , Thanapornsangsuth Poosanu , Tangnimitchoke Suchart , Likitjaroen Yuttachai
Published: December 2023

Background

Anti‐amyloid‐β therapies have been approved to treat mild Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) due to AD. Therefore, diagnosis of AD pathologies is crucial for selecting patients for treatment. Positron emission topography (PET) is used to detect biomarkers for β‐amyloid (A) and tau (T). However, the availability of PET is still limited. Neuropsychological tests may help to select patients who are likely to have AD pathologies. This study aims to select a scale with high performance for AD biomarkers in aMCI patients.

Method

Participants with aMCI were recruited from the Memory Clinic at King Chulalongkorn Memorial Hospital. PET was used to detect AD biomarkers. The Wechsler Memory Scale, Fourth Edition (WMS‐IV) and the Montreal Cognitive Assessment (MoCA) were carried out. We selected four scales which are frequently used to assess AD patients including Visual Reproduction (VR), Logical Memory (LM), and Verbal Paired Associates (VPA) from the WMS‐IV and the Memory Index Scale (MIS) from the MoCA to analyze as predictors. Patients with A+T+ were defined as aMCI with AD biomarkers (aMCI‐AD). Patients with A+T‐ and A‐T‐ were defined as aMCI with non‐pathophysiology of AD (aMCI‐npAD). Multivariable logistic regression was used to construct the predictive model. Area under receiver operating characteristic curve (AUROC) was used to identify the best model in predicting A+T+.

Result

Among 35 participants enrolled (18 aMCI‐AD and 17 aMCI‐npAD), 25 (71.4%) were female. The mean age and education were 71.3±8.1 and 13.8±4.4 years, respectively. The predictive model using LM demonstrated the highest AUROC of 0.84 (95%CI 0.70–0.93), with a sensitivity, specificity, positive predictive value, and negative predictive value of 0.83, 0.71, 0.75, and 0.80, respectively, at the cut‐point with highest accuracy of 77.1%; followed by VR (AUROC 0.78; 95%CI 0.61–0.95), MIS (0.74; 95%CI 0.57–0.91), and VPA (0.68; 95%CI 0.50–0.87).

Conclusion

LM has the highest performance for AD pathologies among the 4 scales to predict AD biomarkers in aMCI. We propose that before undergoing PET, LM may be an appropriate test for selected aMCI patients with a high chance of having AD pathologies.