bluuebunny/crossref_metadata_2025 huggingface dataset:
Self‐report sleep duration associates with plasma Aβ42/40 rate of change in late middle‐aged, African American Adults
Authors: Cook Jesse D , Malik Ammara , Plante David T , Koscik Rebecca Langhough , Du Lianlian , Bendlin Barbara B , Kirmess Kris , Holubasch Mary S. , Meyer Matthew R. , Venkatesh Venky , West Tim , Verghese Philip B. , Yarasheski Kevin E. , Carlsson Cynthia M. , Asthana Sanjay , Johnson Sterling C. , Zuelsdorff Megan , Gleason Carey E.
Published: June 2023

Background

Sleep abnormalities may play a prominent role in the pathogenesis or exacerbation of Alzheimer’s disease (AD). Sleep is considered a modifiable target for prevention and treatment. Racial sleep health disparities exist, and may contribute to the disproportionately increased risk for developing AD associated with being African American. Yet, the relationships between sleep health and AD pathophysiology in African American individuals are under‐studied. This investigation was designed to address research gaps by evaluating the associations of self‐report sleep duration, sleep disturbances, and daytime sleepiness with change in plasma‐derived amyloid β 42/40 ratio (Aβ42/40) in an African American sample.

Method

Archival data from African American participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention study and the Wisconsin Alzheimer’s Disease Research Center were utilized. Data included the Medical Outcomes Study Sleep Scale (MOS‐Sleep), Epworth Sleepiness Scale (ESS), and demographic information. Sleep duration was determined by MOS‐Sleep #2, sleep disturbances were captured by a related MOS‐Sleep subscale (SLPD4), and ESS assessed daytime sleepiness. Participants provided plasma samples across multiple timepoints. PrecivityADTM assays quantified Aβ42/40. Aβ42/40 rate of change (Aβ42/40_ROC) was computed for follow‐up collections to serve as the primary outcome measure. Aβ42/40_ROC was computed as the difference in Aβ42/40 between follow‐up and first collection divided by years between collections. Linear mixed‐effects models determined associations with Aβ42/40_ROC. Observations were nested within participant. Fully adjusted models included age at collection, gender, BMI, education, parental history of dementia, and APOEe4 carrier status.

Result

Data included 339 follow‐up collections from 143 participants. Women provided 70.8% of collections, with average age at collection = 66.6 ± 8.84 years, Aβ42/40_ROC = ‐0.0005 ± 0.003, and sleep duration = 6.35 ± 1.00 hours. Sleep duration significantly associated with Aβ42/40_ROC in the fully adjusted model (β = ‐0.0005; SE = 0.0002; p = 0.02) (Figure 1). Associations between SLPD4 and ESS with Aβ42/40_ROC were nonsignificant.

Conclusion

Longer self‐report sleep duration associated with a steeper reduction rate for plasma Aβ42/40, a biomarker for amyloid pathology. Further research is necessary to clarify the relationships between sleep health components and changes in AD‐related biomarkers within African American adults to identify focal risk factors and interventional strategies.
Methodology dependent sex differences in Aβ‐PET measured with SUVR
Authors: Coath William , Modat Marc , Cardoso M Jorge , Markiewicz Pawel J , Lane Christopher A , Parker Thomas D , Keshavan Ashvini , Buchanan Sarah M , Keuss Sarah E , Harris Matthew J , Bollack Ariane , Burgos Ninon , Dickson John , Barnes Anna , Thomas David L , Beasley Daniel , Malone Ian B , Murray‐Smith Heidi , Wong Andrew , Erlandsson Kjell , Thomas Benjamin A , Schöll Michael , Ourselin Sebastien , Richards Marcus , Fox Nick C , Schott Jonathan M , Cash David M
Published: June 2023

Background

Determining Aβ‐PET status is crucial for Alzheimer’s disease trials. Standard uptake value ratio (SUVR) using a reference region is a common semi‐quantitative technique. Sex differences in regional blood flow and white matter (WM) could impact SUVR differentially depending on the reference region. It is important to understand how methodological factors can influence SUVR derived Aβ status.

Method

Individuals from Insight 46 (1946 British birth cohort) underwent PET/MR scanning with [18F]florbetapir (N = 425; mean age (SD) 70.6 (0.7); 49% female). Regions derived from T1‐weighted MRI with geodesic information flows (GIF) were resampled to PET space. SUVR was calculated (50‐60 mins post‐injection) using a cortical composite target normalised to whole cerebellum (WC) or eroded WM, with/without partial volume correction (PVC). Additionally, SUV was calculated normalising to injected dose and weight. Distribution volume ratio (DVR) from Logan graphical analysis (cerebellar grey matter reference) was calculated for N = 391 (51% female). Linear regression was used to investigate differences in Aβ‐PET measures by sex adjusting for region volumes. Aβ status was defined with Gaussian‐mixture modelling. Sex differences in SUVR and DVR were investigated in individuals rated concordantly Aβ‐ with all four SUVR methods. SUVR Aβ status discordance was examined in relation to sex and APOE e4 genotype.

Result

Females had significantly higher SUVR with a WC reference; and there were no sex differences with a WM reference or with dynamic DVR (Figure 1). Males had higher SUV in all regions and the difference was greater in the WC compared to WM (Figure 2). PVC decreased the influence of volume on SUV in the WC but not WM. 87% of individuals were classified concordantly Aβ+/‐ on SUVR measures with equal proportion of males/females. More females were Aβ+ only with WC reference with PVC, whereas more males were Aβ‐ only on WC without PVC (Figure 3).
Similarities in Pathobiology of Alzheimer’s Disease and Type 2 Diabetes Mellitus: A Proof of Concept by a Case Study
Authors: Noreen Zarish , Mondal Tanmoy , Loffredo Christopher A. , Nunlee‐Blnad Gail , Simhadri Jyothirmai J. , Johnson Jheannelle , Cotin Sharleine T. , Korbe Brent E. , Quartey Ruth , Howell Charles D. , Arif Maria , Bhatti Attya , Chandra Vijay , Jana Siddhartha S. , Shahzad Sharoon , Ghosh Somiranjan Ghosh
Published: June 2023

Background

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Developing countries will have >3 times the prevalence of the developed countries by the year 2050. Our previous studies with a Pakistani population have suggested that type 2 diabetes mellitus (T2DM) is strongly associated with impaired cognitive functioning, and genetic pathways showed strong resemblance to known AD patterns. The present case studies investigated two important pathways, i.e., Amyloid Precursor Protein (APP) processing and Lipid Metabolism, using gene expression profiling arrays to compare and contrast AD and T2DM patients from Pakistan.

Method

We performed high‐throughput qRT‐PCR with preconfigured a TaqMan Low Density Profiling Array specific to Human Alzheimer’s Disease (ABI, CAT # 441887) to measure the altered gene expressions and their corresponding pathways (Ingenuity Pathway Analysis, IPA®). Both the T2DM (n = 2; M/F each) and AD (n = 2, M/F each) patients (cases) were recruited from outpatient departments of a regional hospital, and were compared with their respective matched, healthy controls.

Result

Overall, we observed a differential gene expression profile in AD and T2DM participants compared to controls. CYP46A1, MAPT, CAPNS1, GAL, AGER, CAPN1, PSENEN, ST6GAL1, GRIN2B, GRIN2C, GRIN2A, and GAP43 was downregulated in both T2DM and AD patients. ACHE, CHRM3, GRIN2C and GAP43 significantly (p value <0.05) downregulated in all T2DM patients. CDC2, UCHL1, CTSG, CASP3, IDE, NAE1, CDK5R1, IL6, APBB2, GLS are the top 10 common genes that were upregulated in both AD and T2DM groups. The IPA analysis revealed important Canonical Pathways, that included, viz., Amyloid Processing, Neuroinflammation Signaling, ErB4 Signaling, nNOs Signaling. Molecular Mechanisms of Cancer. The top disease and biofunctions included Metabolic Disease, Neurological disease, Organismal Injury and Abnormalities, Psychological Disorders, Cardiovascular Disease, with the top upstream regulators PHLPP2, IL33, APP, CRP, TAC1.

Conclusion

The differential gene expression patterns and associated disease pathways from this pilot study suggest that specific genes and pathways were common to both diseases and may suggest common underlying processes and causes. Information from such biochemical and genetic studies will be crucial to the development of therapeutic targets to treat AD.
Differential associations between plasma neurofilament light and brain functional connectivity in patients with Alzheimer’s disease and fronto‐temporal dementia
Authors: Chong Joanna Su Xian , Tan Yi Jayne , Koh Amelia Jialing , Zhou Juan Helen , Ng Adeline Su Lyn
Published: June 2023

Background

Neurofilament light chain (NfL), a marker of axonal loss, is elevated in both Alzheimer’s disease (AD) and behavioural variant frontotemporal dementia (bvFTD)[1‐6]. AD and bvFTD have been shown to spread along specific networks reflective of their symptom profiles[7,8], with AD associated with declines in default mode network (DMN) functional connectivity (FC), and bvFTD linked to disruptions in salience network (SN) FC[9]. However, the association between plasma NfL and FC in these two groups remains unknown. Given evidence linking plasma NfL to hypometabolism in circumscribed regions within the DMN in mild cognitive impairment (MCI) patients[10], we hypothesize that NfL would similarly be associated with FC in a network‐specific manner in AD and bvFTD.

Method

Plasma NfL and neuroimaging data from young‐onset patients with bvFTD (n = 16) and AD (n = 38; including AD and MCI of AD type (AD+MCI)) were analyzed. Plasma NfL was measured by single molecule array (SIMOA). Seed‐based FC maps using regions‐of‐interest from DMN (left posterior cingulate cortex) and SN (right anterior insula) were derived for each patient. Voxelwise analyses examining associations between plasma NfL and seed‐based FC were first performed in each group separately. Clusters showing significant FC‐NfL associations were then examined for group differences between AD+MCI and bvFTD, and correlated with neuropsychological performance. All analyses accounted for age, sex, education, handedness and total intracranial volumes.

Results

We demonstrated differential associations between plasma NfL and FC in AD+MCI and bvFTD patients: AD+MCI patients showed significantly lower DMN FC with higher plasma NfL compared to bvFTD patients (Figure 1A), while bvFTD patients showed lower SN FC (Figure 1B) with higher plasma NfL relative to AD+MCI patients. Further, lower NfL‐related DMN FC in AD+MCI patients was significantly associated with lower MoCA scores (Figure 2).

Conclusion

Plasma NfL is associated with FC changes in a network‐specific manner in bvFTD and AD+MCI patients, which may be in turn be predictive of cognitive decline. Our study suggest that axonal protein loss has differential effects on functional brain networks in different dementia subtypes. Future studies are warranted to confirm these findings in a larger cohort.
A unique transgenic model that expressing Aβ oligomers: PS1V97L mutation discovered from Chinese Alzheimer’s disease families
Authors: Quan Meina , Li Xinyue , Wei Yiping , Wang Wei , Xu LingZhi , Li Fangyu , Nie Shuya , Jia Jianping
Published: June 2023

Background

Transgenic mouse models are important tools for studying the pathogenesis of Alzheimer’s Disease (AD) and drug development. Commonly used models are constructed from early‐onset AD mutations in the Caucasian population, and are usually overexpression or knock‐in of multiple pathogenic gene mutations. However, they are not consistent with the genetic characteristics in real world where single gene mutation occurs most of the time. Furthermore, AD transgenic mouse models have been mostly depending on a few institutions/companies and limited by intellectual property protection.

Method

We systematically summarized the research progress of a transgenic mouse model based on a single gene mutation (PS1V97L) found uniquely in Chinese familial AD, as well as the underling mechanisms such as Aβ oligomers (AβO) self‐replication (figure 1). We further compared them with other single‐transgene models, and summarized the preliminary findings of several drugs targeting AβO.

Result

PS1V97L transgenic mice showed age‐related AD phenotypes such as Aβ accumulation, tau phosphorylation, neurofibrillary tangles, gliosis, synaptic degeneration and cognitive impairment (figure 2). The unique characteristics of this model is the aggregation of interneuronal AβO in cortex and hippocampus, but no plaques formed up to 24 months. Other mechanisms of PS1V97L model include oxidative stress, inflammation, abnormal energy metabolism, and alterations in AD‐related signaling pathways, such as PI3K/Akt and Nrf2/ARE pathways. Several drugs including sulforaphane, honokiol, tenuifolin, isoliquiritigenin, ginsenoside, butylphthalide and oxiracetam were found effective in PS1V97L mouse model as well as rat and cell models based on AβO mechanism.

Conclusion

Although carrying only one mutation, PS1V97L transgenic mouse model can mimic almost all AD pathological phenotypes, and supports AβO pathogenic hypothesis. It provides important basic and translational tool for exploring the upstream mechanisms, risk factors, and multi‐target drug development in AD.
Simultaneous mediation effect estimation of APOE through multiple neuropathological pathways on cognitive outcomes
Authors: Xia Fan , Culhane Jessica E. , Chan Kwun Chuen Gary , Keene C. Dirk , Kukull Walter A.
Published: June 2023

Background

Individual associations of APOE genotype with Alzheimer’s disease neuropathologic changes (ADNC) have been studied extensively, but the effects through comorbid neuropathological pathways are rarely evaluated simultaneously. In addition, conventional statistical methods for mediation analysis rely heavily on assumptions on causal directions among different pathologies.

Method

Using the National Alzheimer’s Coordinating Center database, we use state‐of‐the‐art mediation analysis methods for multiple mediators effect decomposition to simultaneously estimate the indirect effects of the APOE ε4 allele through different pathologies, including ADNC, TDP‐43, and Lewy body disease, on cognitive outcomes. Unlike the conventional Baron and Kenny approach, we do not assume a causal structure between different pathologies, making causal interpretations under fewer assumptions. We control for cerebrovascular diseases, cardiovascular diseases, and age at death that are potentially affected by the APOE ε4 allele and could confound the pathologies.

Result

Our results show that the APOE ε4 allele has a negative effect on cognitive outcomes (MoCA: ‐4.97 (‐6.92, ‐3.03); CDR Sum of Boxes: 1.34 (0.70, 1.98)). Most of the effect goes through ADNC (MoCA: ‐3.37 (‐4.68, ‐2.05); CDR Sum of Boxes: 1.20 (0.92, 1.49)), and there is evidence that the indirect effect through ADNC is significant for both outcomes. There is a small indirect effect through TDP‐43 pathology of the same direction as the total causal effects. It is significant for the standard CDR sum of boxes (0.26 (0.13, 0.39)) but not for the MoCA score (‐0.37 (‐0.81, 0.07)). There is little evidence of an indirect effect through Lewy body pathology for both outcomes. In addition, the effect that goes through the dependence or interaction between the pathologies is small.

Conclusion

We utilize novel causal mediation analysis methods on neuropathology data to quantify the effects of APOE genotype on dementia risk through different ADRD pathologies without requiring knowledge of their causal relationship. Most of the effect of the APOE ε4 allele goes through ADNC, as expected, but there is also evidence of a smaller indirect effect through TDP‐43. This work provides insights into the understanding of the dementia disease process and introduces a new statistical tool for future AD and related dementias research.
Midlife insulin resistance, APOE genotype, and change in late‐life brain amyloid accumulation – a 5‐year follow‐up 11C‐PIB‐PET study
Authors: Pietilä Elina M. , Ekblad Laura L. , Snellman Anniina , Toppala Sini , Tuisku Jouni , Helin Semi , Viitanen Matti , Jula Antti , Rinne Juha O.
Published: June 2023

Background

Midlife insulin resistance has been associated with an increased risk for cognitive decline (1) and amyloid accumulation (2). We hypothesized that midlife insulin resistance would predict amyloid accumulation 20 years later, and the change in brain amyloid accumulation during the 5‐year imaging follow‐up.

Methods

We studied 60 cognitively normal participants from the Finnish population‐based Health2000 study in 2014‐2016 with 11C‐PIB‐PET (2). They were recruited according to their homeostatic model assessment of insulin resistance (HOMA‐IR) values measured 15 years earlier in 2000, and their APOEε4 genotype. The insulin resistance group (IR+, HOMA‐IR <1.25) and the control group (IR−, HOMA‐IR > 2.17) both included 30 participants and 50% APOEε4 carriers. In 2019‐2021 43 participants took part in the 5‐year 11C‐PIB‐PET‐imaging follow‐up. Here, we report the change in amyloid accumulation in the IR+ group (n = 19, 57% APOE ε4 carriers) and the IR‐ group (n = 24, 46% APOEε4 carriers) during this 5‐year interval. 11C‐PIB‐PET images were analyzed with an in‐house pipeline and standard uptake value ratio (SUVR) composite scores were calculated. Kruskal‐Wallis test and the Steel‐Dwass method was used to analyze the difference in amyloid accumulation rates between groups, and Spearman’s correlation was utilized to assess the association between HOMA‐IR and amyloid accumulation.

Result

At the 20‐year follow‐up, amyloid accumulation was significantly higher in the IR+ group than the IR‐ group (composite SUVR 2.43 vs. 1.96, p = 0.03) (Fig. 1). The change in amyloid accumulation during 5 years was significantly higher in the IR+/APOEε4+ group than in either IR−/APOEε4− (mean change in composite SUVR 0.79 vs. 0.32, p = 0.02) or IR+/APOEε4− groups (mean change in composite SUVR 0.79 vs. 0.26, p = 0.046,) (Fig. 2). HOMA‐IR in 2000 (rS = 0.39, p = 0.01) and 2014‐2016 (rS = 0.34, p = 0.03), but not in 2019‐2021 (rS = 0.24, p = 0.13), correlated with 11C‐PIB composite SUVR at the 20‐year follow‐up.

Conclusion

These results suggest that IR could be an additive risk factor for late‐life amyloid accumulation in APOEε4 carriers, and that midlife, but not late‐life IR associates with amyloid accumulation.

1) Ekblad et al., Diabetes Care 2017

2) Ekblad et al., Neurology 2018
Interaction between APOE4 and lifestyle on neuroimaging biomarkers and cognition in cognitively unimpaired older adults
Authors: Felisatti Francesca , Chauveau Léa , de Flores Robin , Marchant Natalie L , Collette Fabienne , Demnitz‐King Harriet , Whitfield Tim , Requier Florence , Palix Cassandre , Haudry Sacha , Delarue Marion , la Sayette Vincent De , Vivien Denis , Poisnel Géraldine , Chetelat Gael , Gonneaud Julie
Published: June 2023

Background

APOE4 is the main genetic risk factor for Alzheimer’s disease (AD). Recent findings suggest that lifestyle factors could modulate the association between APOE4 and cognitive impairment and/or dementia risk. However, a comprehensive assessment of the interactions between lifestyle and APOE4 status on neuroimaging and cognitive markers of aging and AD is still missing. Our objective is to assess this question in cognitively normal elderly.

Method

Baseline data of 134 cognitively unimpaired older adults (mean age: 69) from the Age‐Well study were analysed. They underwent lifestyle questionnaires (physical and cognitive activity, and diet), neuropsychological assessment (global cognition, memory, attention and executive functions) and multimodal neuroimaging (structural MRI, FDG‐ and Florbetapir‐PET). Interactions between lifestyle and APOE4 status on neuroimaging and cognition were assessed for each lifestyle factor separately.

Result

There was an interaction between APOE4 status and cognitive activity on neuroimaging measures (p‐values<.04), such that higher cognitive engagement was associated with lower grey matter volume in the parahippocampal cortex and lower brain perfusion in the entorhinal and perirhinal cortices in APOE4 carriers only (Figure 1A). However, greater cognitive engagement was associated with increased cognitive performance (global cognition, executive function and attention, all p‐values<.005), and this irrespective of APOE4 status (i.e., no cognitive activity x APOE4 status interaction; Figure 1B). For diet, interactions were evidenced (p‐values <.04) such that higher adherence to the Mediterranean diet was associated with i) higher brain glucose metabolism in the medial temporal lobe (Figure 2A) and ii) higher performance on attention tests (Figure 2B) in APOE4 carriers only. No interactions were found for physical activity.

Conclusion

Our results indicate that APOE4 carriers with higher cognitive activity had lower brain outcomes but preserved cognition, suggesting that enriched cognitive engagement promotes cognitive resilience in this population. On the other hand, APOE4 carriers with higher adherence to the Mediterranean diet had greater cerebral metabolism and greater attention capacities. Overall, this suggests that distinct lifestyle factors differentially help APOE4 carriers to resist or cope with brain alteration and postpone cognitive decline.

ClinicalTrials.gov Identifier: NCT02977819.
Sleep, physical activity, sedentary behavior, and risk of incident dementia: A prospective cohort study of 431,924 UK Biobank participants
Authors: Huang Shu‐Yi , Yu Jin‐Tai
Published: June 2023

Background

Sleep, physical activity (PA), and sedentary behavior have been individually associated with the risk of dementia, but findings are inconsistent. Their joint associations with dementia also remain unknown. We aimed to investigate the independent and joint associations of sleep duration, PA, and sedentary behavior with dementia risks and the underlying mechanisms.

Method

A total of 431,924 participants with a median follow‐up 9.0 years from UK Biobank without dementia were included. Cox proportional hazards regression was performed to test the independent and joint association of sleep, PA, and screen‐based sedentary behavior with dementia. We also test the non‐linearity of these associations. Non‐linear regression was performed to examine the associations of each behavior with brain morphometric measures.

Result

During a median observation follow‐up period of 9.0 years, 5390 participants developed an incident dementia among 431,924 individuals. Sleep duration, leisure‐time PA, and screen‐based sedentary behavior individually associated with dementia risks in different non‐linear association modes. Sleep duration associated with dementia risk in a U‐shape, and participants with a seven‐hour sleeping pattern showed the lowest dementia risk. Leisure‐time PA associated with dementia in a curvilinear relationship with diminishing returns, and sedentary behavior associated with dementia in a J‐shaped association. The dementia risk was 17% lower in the high leisure‐time PA group ((95%CIs), 0.83 (0.76‐0.91)) and 22% higher in the high sedentary behavior group (1.22 (1.10‐1.35)). A combination of seven‐hour sleep, moderate‐to‐high leisure‐time PA, and low‐to‐moderate sedentary behavior showed lower dementia risks (0.66 (0.56‐0.78)) compared to the referent group with atypical sleep, low leisure‐time PA, and high sedentary behavior. Notably, each of the three behaviors was non‐linearly associated with brain morphometric measures in the similar modes as their associations with dementia. Proper intensity/time‐spent on each behavior of interest was associated with higher brain volumes. The relationship of each behavior with dementia was partially mediated by cerebrovascular diseases.

Conclusion

A 7‐hour/day sleep duration, higher leisure‐time PA, and lower sedentary behavior are independently and jointly associated with lower dementia risks. Our findings underscore the potential of changing these three daily behaviors concomitantly to mitigate dementia risks in population‐wide strategies.
The burden of COVID‐19 on all‐cause mortality in older adults living in Wales
Authors: Lai Helen , Kolanko Magdalena A , North Laura , Akbari Ashley , Tzoulaki Ioanna , Sharp David J , Soreq Eyal
Published: June 2023

Background

The COVID‐19 pandemic has profoundly impacted the lives of people living with dementia (PLWD). Mitigating measures have led to extreme social isolation and reduced or limited capacity within routine health and social care services. Using anonymised individual‐level, population‐scale linked electronic healthcare, demographic and mortality records in Wales, we have examined the impact of the COVID‐19 pandemic on all‐cause mortality in PLWD and in older adults living with other comorbid conditions.

Method

Using the Secure Anonymised Information Linkage (SAIL) Databank (Lyons et al., 2009), we identified six cohorts of individuals aged 50‐101 and living in Wales on or before 1st February 2020, with conditions in the following domains: dementia, cardiovascular, respiratory, metabolic, renal, and cerebrovascular. For each, we identified paired samples matched by age and sex using propensity sampling. Evidence for comorbidities were extracted using ICD‐10 and READ codes. We quantified excess mortality in PLWD during the COVID‐19 period (July 2020 – May 2021 at the point of the analysis) by comparing weekly mortality to a baseline rate (2015‐2019 average) and to the population paired sample. We then extracted retrospective datasets across sixteen‐month periods from 2010‐2020. Finally, we estimated all‐cause mortality odds‐ratios for each period and comorbid domain using logistic regression, controlling for age and sex.

Result

PLWD had higher risk of all‐cause mortality compared to a matched sample of individuals without dementia (Figure 1a), especially during the first wave of the pandemic (April 2020, Figure 1b), and in older PLWD (Figure 1c). Examining evidence across other comorbid conditions (Figure 2), logistic regression modelling showed the greatest increase in mortality odds among PLWD (Figure 2f) compared to people without dementia, increasing from 4.47 in 2018 to 5.61 in 2020. The magnitude of the increase in odds among people with cardiovascular, metabolic, renal, and cerebrovascular conditions from 2020‐2021 compared to previous years was smaller compared to the increase in PLWD (Figures 2a, 2c‐e).

Conclusion

PLWD experienced increased mortality risk compared to those living with other comorbid conditions during 2020. Further work will focus on the composition of death causes and the contribution of other comorbidities to all‐cause mortality among PLWD.
Brain neural synchronization mechanisms are affected by aging in cognitively unimpaired seniors and patients with Alzheimer’s disease and mild cognitive impairment
Authors: Percio Claudio Del , Lizio Roberta , Noce Giuseppe , Lopez Susanna , Soricelli Andrea , Ferri Raffaele , Tucci Federico , Güntekin Bahar , Yener Görsev , Frisoni Giovanni B , Babiloni Claudio
Published: June 2023

Background

The resting state eyes‐closed electroencephalographic (rsEEG) alpha (8‐12 Hz) rhythms reflect cortical neural synchronization mechanisms underpinning the inhibition of sensory, cognitive, and motor areas in parietal, temporal, and occipital cortex during a condition of low vigilance. Here we tested the hypothesis that age may diversely affect rsEEG alpha (8‐12 Hz) rhythms recorded in normal elderly (Nold) seniors and patients with Alzheimer’s disease and mild cognitive impairment (ADMCI).

Method

Clinical, magnetic resonance imaging (MRI) and rsEEG datasets in 63 ADMCI and 60 Nold individuals were taken from an international archive. The rsEEG rhythms were investigated at individual delta, theta, and alpha frequency bands as well as fixed beta (14‐30 Hz) and gamma (30‐40 Hz) bands. Each group was stratified into three subgroups based on age ranges (i.e., tertiles).

Result

As compared to the younger Nold subgroups, the older one showed greater reductions in the rsEEG alpha rhythms with major topographical effects in posterior regions (Figure 1). On the contrary, in relation to the younger ADMCI subgroups, the older one displayed lesser reduction in those rhythms (Figure 1). Furthermore, a decrease in the total grey matter (GM) volume and total cortical thickness as well as an increase in the white matter (WM) hypointensity were found in the older ADMCI subgroups compared to the younger ADMCI subgroups (Figure 2).

Conclusion

The results of the present study suggest that in Nold seniors, the aging factor may significantly affect neurophysiological brain neural synchronization mechanisms underpinning the generation of dominant rsEEG alpha rhythms. In contrast, rsEEG alpha rhythms in ADMCI patients may be more affected by the disease variants, with more deleterious effects observed in early‐ than the late‐onset ADMCI patients. In the ADMCI patients, the mere effects of the aging factor may be hidden by dysfunctions in subcortical structures, including the cholinergic basal forebrain and thalamus.
Decreased activities of prefrontal and temporal lobes in patients with mild cognitive impairment and mild Alzheimer’s disease on a clock drawing task via functional near‐infrared spectroscopy imaging
Authors: Zhong Fuxin , Zhang Wenbo , Lü Yang
Published: June 2023

Background

Studies have shown that changes in cerebral blood flow occur in the early stage of dementia, including Alzheimer’s disease (AD), and decreased cerebral blood flow contributes to impairment of brain activities, then affects cognitive function. To diagnose AD in very early stage, such as mild cognitive impairment (MCI), it is therefore necessary to find a new way to detect early activities of brain, such as functional near‐infrared spectroscopy (fNIRS).

Methods

The clock drawing task (CLOX) is one of the widely used neurocognitive function scoring test for dementia. In this study, brain activities were examined in patients with MCI (n = 8) and mild AD (n = 8) during an unprompted CLOX drawing using functional near‐infrared spectroscopy (fNIRS). The concentration changes of oxyhemoglobin (HbO), reflecting brain activities indirectly, were tested in each group via fNIRS.

Results

Activation in the right hemisphere was significantly attenuated in mild AD compared with MCI. With the development of disease severity from MCI to mild AD, the reductions of HbO2 concentrations in the right prefrontal and right temporal lobe were observed greater and steeper. The HbO2 in mild AD was significantly lower than that in MCI (false discovery rate corrected, p <0.025). In addition, HbO2 concentration was positively associated with the clinical score of MMSE (MCI group, p<0.05; mild AD group, p<0.05).

Conclusion

This study suggests that activity in the frontal and temporal lobes of mild AD is reduced compared to MCI. Those results reflects that CLOX is an effective tool for extracting fNIRS signal features. In addition, fNIRS‐based analysis has great promise for exploring the mechanisms of changes in the sensory‐spatial function of MCI and mild AD.
The impact of dance‐movement interventions on psychological health in older adults: A systematic review and meta‐analysis of randomized controlled trials
Authors: Zarucha Alexis , Podolski Odile Sophie , Schaaf Leah , Cassing Vilana , Whitfield Tim , Wirth Miranka
Published: June 2023

Background

Good psychological health is proposed as a key factor in the protection against Alzheimer’s disease (AD) and age‐related cognitive decline1. Multimodal motor, cognitive, sensory, and social enrichment as induced by dance‐movement interventions (DMI) could promote psychological health in the older population. This systematic review and meta‐analysis investigated the impact of DMI compared to control intervention (active/passive) on psychological health in older adults.

Methods

A systematic search of three databases (PubMed, Web of Science, PsycInfo; screenings: April and November 2021) was conducted following PRISMA guidelines. Criteria included randomized controlled trials (RCTs) evaluating the effects of DMI (minimum 4 weeks’ duration) on health‐related psychological outcomes (primary outcome) and global cognitive functioning (secondary outcome) among non‐demented older adults (≥ 55 years of age). A random‐effects meta‐analysis with robust variance estimation was carried out. This review was registered with PROSPERO (CRD42021265112).

Results

Data of 13 eligible primary RCTs (n = 943, n‐DMI = 474, n‐control = 469) were synthesized. Overall heterogeneity of results and risk of bias across RCTs were high. DMI had a small positive impact on psychological health compared to control (g = 0.31; 95% Confidence Interval (CI): [0.09, 0.53]; p = .01, I2 = 62.55). Separation of psychological health into positive and negative outcomes and particularly social and emotional aspects showed similar trends favouring DMI compared to control (see Figure 1). Analysis of secondary outcomes indicated a positive effect of DMI on global cognitive functioning (g = 0.48; 95%CI: [0.03, 0.93], p = .04, I2 = 82.44). Exploratory subgroup analyses suggested that the implementation of longer intervention durations and psychotherapeutic elements increase the psychological health benefits of DMI.

Conclusion

Multimodal interventions, as specifically offered by DMI, may serve as an effective tool to promote psychological health together with cognitive functioning in older adults. High‐quality future trials are needed to expand evidence on the particular aspects of psychological health and identify underlying neurophysiological correlates. We will present a protocol for a prospective RCT to assess the impact of a DMI on psychological, cognitive and brain health outcomes in the older population at increased risk of AD.

References

1Livingston G, et al. Lancet 2020.
Cross‐sectional and longitudinal associations of plasma makers of amyloid and tau pathology and neurodegeneration with gait speed
Authors: Syrjanen Jeremy A. , Vemuri Prashanthi , Graff‐Radford Jonathan , Machulda Mary M. , Knopman David S. , Petersen Clifford R. JackRonald C. , Mielke Michelle M.
Published: June 2023

Background

Higher brain amyloid PET is associated with slower gait speed and has been hypothesized to play a role in age‐related mobility decline. With the development of blood‐based biomarkers of Alzheimer’s disease pathology, we examined whether plasma levels of amyloid‐beta (Aβ)40, Aβ42, the Aβ42/Aβ40 ratio, phosphorylated tau 181 (p‐tau181) and 217 (p‐tau217), total tau, and neurofilament light chain (NfL) were associated with gait speed.

Method

This study included 779 cognitively unimpaired participants (median age 75, 54.8% male, median follow‐up 6.8 years) in the Mayo Clinic Study of Aging with concurrent measurement of plasma biomarkers and gait speed. Individuals with chronic kidney disease or a history of stroke were excluded. The plasma markers (pg/mL) were measured on the Quanterix Simoa® HD‐1 analyzer (total tau, Aβ42, Aβ40, NfL) and the Meso Scale Discovery platform (p‐tau181, p‐tau217). Gait speed (m/s) was obtained by timing a self‐paced walk across 25 ft using a stopwatch. Linear mixed effects models, with subject‐specific intercepts and slopes for time since baseline, with z‐scored baseline plasma markers were used to predict cross‐sectional and longitudinal gait speed. All models adjusted for baseline age and sex.

Result

At baseline, higher Aβ42 [Beta = ‐0.019; 95%CI = (‐0.035, ‐0.004)], total‐tau [‐0.026; (‐0.041, ‐0.011)], and p‐tau181 [‐0.021; (‐0.036, ‐0.006)] were associated with slower gait speed. Gait speed decreased, on average, by about 0.015 m/s annually for those in this study. Each one standard deviation (SD) increase in baseline level of plasma Aβ40 [‐0.005; (‐0.007, ‐0.002)], NfL [‐0.006; (‐0.009, ‐0.004)], and p‐tau217 [‐0.004; (‐0.007, ‐0.001)] accelerated this decline over time. In contrast, each one SD increase in Aβ42/Aβ40 ratio [0.003; (0.001, 0.006)] mitigated decline. Additional analyses adjusting for Charlson comorbidity index, Beck Depression Inventory, body mass index, and APOE E4 allele status gave similar results.

Conclusion

Both cross‐sectional and longitudinal associations of plasma markers of amyloid and tau pathology and neurodegeneration with gait speed among cognitively unimpaired individuals were present. Therefore, not only are these markers of cognitive changes, they are also related to motor changes such as those affecting gait speed.
Apolipoprotein C proteins in plasma non‐high‐density lipoprotein fractions and development of Alzheimer’s disease, central arterial stiffness, and cerebral small vessel disease in older adults
Authors: Glittenberg Matthew , Flaten Zachery , Kumar Sai Kaushik Shankar Ramesh , Li Danni
Published: June 2023

Background

Plasma non‐high‐density lipoproteins impact development of central arterial stiffness and cerebral small vessel disease (cSVD), significantly contributing to Alzheimer’s disease (AD) and related dementias (ADRDs) through an increase in cerebral amyloid beta (Aβ) burden and acceleration of atrophy in susceptible brain regions. We sought to identify proteins in three non‐HDL plasma lipoproteins (very‐low density lipoprotein [VLDL], intermediate‐density lipoprotein [IDL], low‐density lipoprotein [LDL]) and their cross‐sectional associations with brain amyloid deposition, central arterial stiffness, neuroimaging features of cSVD (e.g., white matter hyperintensity volume), brain volumes susceptible to AD and cSVD, and incidence of dementia.

Method

Plasma samples from 66 participants of the Atherosclerosis Risk in Communities (ARIC) study were fractionated to isolate VLDL, IDL, and LDL and analyzed using label‐free liquid chromatography‐mass spectrometry (LC‐MS) with Data‐Independent Acquisition. Acquired MS spectra were processed using Spectronaut™ to give protein identification and relative protein abundances were calculated using R. Linear regression models were used to examine the cross‐sectional associations between protein abundances in VLDL, IDL or LDL and brain amyloid deposition (measured by amyloid PET scan), white matter hyperintensities (WMH) volume (measured by brain MRI), central arterial stiffness (carotid‐femoral and heart‐femoral pulse wave velocity), AD‐signature region, frontal, parietal, and hippocampal brain region volumes (measured by brain MRI), and incidence of dementia. Regression models were adjusted for age, sex, race, number of APOε4 alleles, and cholesterol level (if applicable). Additionally, differential analysis (student’s t‐test) was used to compare protein abundances in non‐HDL lipoproteins between participants with elevated versus normal brain amyloid deposition.

Result

We identified 50, 78, 81 proteins in VLDL, IDL, and LDL, respectively. The most significant findings were: 1) higher levels of apolipoprotein C proteins in VLDL, IDL, and LDL were associated with lower WMH volume or less central arterial stiffness; 2) lower levels of apolipoprotein C proteins in VLDL, IDL, and LDL were associated with less incidence of dementia; 3) lower levels of apolipoprotein C proteins in VLDL, IDL, and LDL for participants with elevated amyloid deposition.

Conclusion

These results suggest the possible role of apolipoprotein C proteins present in non‐HDL‐lipoproteins in the development of AD, central arterial stiffness, and cSVD.
Overexpression of Aha1 and FKBP52 does not affect learning or mood‐like behavior in human tau (hTau) mice
Authors: Criado‐Marrero Marangelie , Esquivel Abigail R. , Blair Laura J.
Published: June 2023

Background

Tau plays a critical role in neurodegeneration, thus targeting this protein to control its accumulation is important to prevent or delay neurotoxicity in tauopathies like Alzheimer’s disease (AD). Discrete molecular chaperones, like Aha1 and FKBP52, are known to affect the stability of tau by promoting its phosphorylation, aggregation and, in some mouse models, neuronal death. However, one limitation of preclinical tau models is that various contain tau mutations which do not represent most AD cases. Our study is important because it investigates biological mechanisms and behavioral phenotype in a humanized tau (hTau) mouse model absent of tau mutations. We hypothesize that overexpression of Aha1 in in hTau mice will accelerate tau tangle formation and cognitive deficits.

Method

To test this, Tau KO and hTau mice were bilaterally injected into the hippocampus with AAV9‐Aha1, AAV9‐FKBP52, and AAV9‐mKate (control) virus. At 11 and 13 months of age, animals were tested for cognitive and behavioral phenotypes.

Results

We found that overexpression of these chaperones does not affect anxiety, spatial working memory, and locomotion in hTau mice. We further confirmed that short‐term working memory in the learning and extinction of fear memories remained unaltered by the high levels of Aha1 and FKBP52 at these ages. Ongoing analyses will examine tau pathology in these brains by measuring tau levels, neuronal density, and cell death markers.

Conclusion

At this timepoint, Aha1 and FKBP52 did not induce behavioral differences in these mice. We recently reported that overexpression of these chaperones promotes tau pathological changes in 16‐months‐old wild‐type. Thus, it is possible that behavioral differences can be detected as tau pathology progresses at an older age.
What a single electroencephalographic (EEG) channel can tell us about Alzheimer's disease patients with mild cognitive impairment
Authors: Tucci Federico , Percio Claudio Del , Lopez Susanna , Noce Giuseppe , Lizio Roberta , Soricelli Andrea , Ferri Raffaele , Nobili Flavio , Arnaldi Dario , Famà Francesco , Buttinelli Carla , Giubilei Franco , Marizzoni Moira , Güntekin Bahar , Yener Görsev , Stocchi Fabrizio , Vacca Laura , Frisoni Giovanni B , Babiloni Claudio
Published: June 2023

Background

Abnormalities in the neurophysiological oscillatory mechanisms generating dominant resting‐state eyes closed electroencephalographic (rsEEG) rhythms portray the Alzheimer’s disease (AD) continuum, from the preclinical to the dementia stage. Here, we tested whether these abnormalities may be reproducible by analyzing the rsEEG signals acquired in bipolar configuration with a montage consisting of only four centro‐parietal and parieto‐occipital channels (C3‐P3, C4‐P4, P3‐O1, and P4‐O2) in patients with mild cognitive impairment (MCI) due to AD (ADMCI).

Method

To evaluate the study hypotheses, clinical, neuropsychological, anthropometric, genetic, cerebrospinal fluid (CSF), MRI, and rsEEG data in 70 Nold and 75 ADMCI subjects from an international archive were used in the present study. The subgroups were matched for age, gender, and education. In all subjects, rsEEG recordings lasted about 3‐5 minutes. The rsEEG data were recorded with a sampling frequency of 128‐512 Hz and related antialiasing bandpass between 0.01 Hz and 60‐100 Hz. Electrode montage included 19 scalp monopolar sensors placed following 10‐20 System. The rsEEG rhythms were investigated at individual delta, theta, and alpha frequency bands as well as fixed beta (14‐30 Hz) and gamma (30‐40 Hz) bands.

Result

Results confirmed previous evidence about the abnormalities of the delta, theta, and alpha rhythms in ADMCI patients compared to Nold subjects. Moreover, as compared to the Nold group, the ADMCI group showed increased delta power density and decreased alpha power density at the C3‐P3, C4‐P4, P3‐O1, and P4‐O2 bipolar channels. Increased theta power density for ADMCI patients was observed only at the C3‐P3 bipolar channel. Best classification accuracy between the ADMCI and Nold individuals reached 81% (area under the receiver operating characteristic curve) using Alpha2/Theta power density computed at the C3‐P3 bipolar channel.

Conclusion

The current findings provide evidence in the potential use of rsEEG low‐channel portable devices as a topographic biomarker of cognitive decline within the extensive screening of in elderly population at risk of developing AD‐ or other dementia‐related disorders. Moreover, the confirmation of this hypothesis would have exciting applications in the framework of telehealth home monitoring of global brain functions.
Hippocampal subfields’ sex differences in EOAD
Authors: Contador José , Pérez‐Millan Agnés , Guillén Núria , Sarto Jordi , Tort‐Merino Adrià , Balasa Mircea , Martínez Neus Falgàs , Castellví Magdalena , Borrego‐Écija Sergi , Juncà‐Parella Jordi , Bosch‐Capdevila Beatriz , Fernandez‐Villullas Guadalupe , Ramos‐Campoy Oscar , Antonell Anna , Bargalló Núria , Sanchez‐Valle Raquel , Sala‐Llonch Roser , Lladó Albert
Published: June 2023

Background

In healthy ageing, there is evidence of sex differences in vulnerability of hippocampal subfields to volume loss. However, this has not been investigated in early‐onset Alzheimer’s disease (<65 years; EOAD).

Method

We included 106 subjects: 62 EOAD (A+T+N+, MMSE>15) and 44 healthy controls (HC; A‐T‐N‐) that underwent lumbar puncture for analysis of AD biomarkers, 3T‐MRI scan and neuropsychological assessment. Hippocampal subfield segmentation was performed using T1‐weighted images and Freesurfer 6.0. Volume was adjusted by intracranial volume. Adjusted linear models were used to analyze differences between EOAD and HC and differences between sexes. We calculated Cohen’s d as a measure of the effect size of volume change by sex, restricted to volume differences between EOAD and HC. In EOAD, we used linear models adjusted by age and education to investigate the association of volume loss with 18 cognition z‐scores. Results were adjusted using Bonferroni correction for multiple comparisons.

Result

There were no demographic differences across groups. APOEε4 carriers were higher in EOAD‐female/EOAD‐male than HC‐female. EOAD‐female showed higher T‐Tau and P‐Tau levels than EOAD‐male (all p<0.05; Table1). Comparing EOAD vs. HC, differences were found in volume of all subfields and hippocampus (p<0.05, Bonferroni corrected), except for bilateral parasubiculum and right cornu ammonis (CA) 2/3. No differences were found between EOAD‐female and EOAD‐male (p>0.05). When compared to HC of the same sex, EOAD‐female showed differences in the same regions as the whole sample, while EOAD‐male showed differences in bilateral hippocampal tail and left presubiculum and hippocampus (all p<0.05, Bonferroni corrected, Figure 1). We observed larger effect sizes than in women in these regions, except for left hippocampus (Figure 2).

In EOAD, higher volume in left CA2/3 predicted higher memory z‐scores, including free and total learning and delayed total recall (p<0.05 Bonferroni corrected; Figure 3). No associations were found in EOAD‐female nor EOAD‐male.

Conclusion

In EOAD, the pattern of volume loss in hippocampal subfields was similar between sexes. However, females showed more marked differences from HC, except for bilateral hippocampal tail and left presubiculum. Further studies are necessary to elucidate the existence of sex differences in EOAD and their implication for cognitive impairment.