bluuebunny/crossref_metadata_2025_split huggingface dataset:
Facilitating clinical use of the Amsterdam instrumental activities of daily living questionnaire: Dutch normative data and clinical cutoff values
Authors: Postema Merel C. , Dubbelman Mark A. , Verrijp Merike , Visser Pieter Jelle , Zwan Marissa D. , van der Flier Wiesje M. , Sikkes Sietske A.M. 
Published: June 2023

AbstractBackgroundThe Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q) is a proxy‐based instrument aimed at measuring difficulties in daily functioning due to cognitive decline in the context of dementia. To facilitate its interpretation and clinical implementation, normative data from the general population are necessary. Here, we aimed to compose normative scores for the A‐IADL‐Q and provide clinical cutoff values for mild cognitive impairment (MCI) and dementia.MethodCross‐sectional data from three Dutch cohorts (i.e., Dutch Brain Research Registry, European Medial Information Framework‐Alzheimer’s Disease (EMIF‐AD) 90+, and Amsterdam Dementia Cohort (ADC)) were used, including 1127 cognitively healthy individuals and 380 individuals with MCI and/or dementia. Regression‐based norms were constructed in the healthy sample, using linear models including age, sex, education(high/low) and their interactions, and the optimal model was selected using backward elimination. Individual differences between observed and expected IADL t‐scores were divided by the residual standard error of the model. Optimal normative score cutoffs to distinguish healthy from MCI and/or dementia were based on bootstrap average estimates(500 repeats) of the Youden Index. Diagnostic accuracy was evaluated using receiver operating curves (ROC), area under the curve (AUC), sensitivity and specificity.ResultNormative data (mean age = 64±13year, 68.6%female, 67.8% highly educated) and memory clinic data (mean age = 66±8year, 43.9%female, 38.9% highly educated) were used (Table1). The best normative model (i.e., with the lowest Akaike information criterion) included age‐squared, sex, education and the interaction between age and education. The optimal normative score cutoffs to distinguish healthy from dementia and MCI/dementia were, respectively, 1.78SD and 1.79SD below the mean, with high AUCs of 0.96 [95%CI 0.95‐0.98] and 0.94 [95%CI 0.92,0.95]. The optimal cutoff to distinguish healthy from MCI was higher; 1.01SD below the mean, also with a high AUC‐score of 0.86 [95%C 0.81‐0.9])(Table2, Figure1).ConclusionWe composed normative scores with clinical cutoff values that can aid in the distinction between cognitively healthy from MCI and/or dementia with high diagnostic accuracy. These normative scores are accessible via an online tool to further facilitate and implement clinical use of the A‐IADL‐Q. Future studies should include participants from different countries, cultures and different socio‐economic background to facilitate world‐wide use.
Associations of cortisol with neuroinflammation biomarkers in a memory clinic cohort
Authors: Daniilidou Makrina , Hagman Göran , Holleman Jasper , Sindi Shireen , Solomon Alina , Sandebring‐Matton Anna , Kivipelto Miia 
Published: June 2023

AbstractBackgroundCortisol, one of the most important mediators of stress in humans, is often found increased in Alzheimer’s disease (AD) patients and correlates with disease severity. Stress response and inflammation are two systems that are tightly associated to one another. Several lines of evidence suggest that cortisol can promote inflammation. However, less is known on the interaction of cortisol with neuroinflammation in the context of AD, and to the best of our knowledge there are no human studies that have systematically explored the association of these two systems in AD patients so far. The aim of this study was to investigate levels of cerebrospinal fluid (CSF) biomarkers of neuroinflammation and their relationship to salivary cortisol in a memory clinic cohort.MethodA total of 108 memory clinic patients with subjective cognitive decline (SCI, n = 40), mild cognitive impairment (MCI, n = 39) and AD (n = 29), from the Karolinska University Hospital in Stockholm, Sweden, were included in this study. Salivary cortisol was collected at six timepoints during the day on two days, to quantify awakening cortisol, cortisol awakening response (CAR), bedtime cortisol and total cortisol. CSF levels of 37 neuroinflammation and cerebrovascular dysfunction biomarkers were determined by a multiplex immunoassay. Associations among cortisol and neuroinflammation markers were assessed by linear regression models adjusting for age and diagnosis. ANCOVA tests were used to compare biomarker levels between the diagnostic groups.ResultAwakening cortisol was significantly elevated in the AD group compared to the SCI and MCI participants. Higher IP‐10 and placental growth factor (PlGF) levels were associated with decreased CAR independent of age and diagnosis. Thymus and activation‐regulated chemokine (TARC), CRP, intracellular adhesion molecule 1 (ICAM‐1) and vascular cell adhesion molecule 1 (VCAM‐1) levels were upregulated in MCI participants compared to SCI and AD.ConclusionWe provide evidence that the HPA axis is altered in AD. Moreover, salivary cortisol is associated to neuroinflammation in an age and diagnosis independent manner. Finally, neuroinflammatory and vascular dysfunction regulators are increased in CSF during MCI stages followed by a drop in their levels in AD participants, presumably reflecting a more active role of neuroinflammation at an early state.
A systematic review on the effects of tACS on cognitive function within older adults
Authors: Kraft Jacob D , Hampstead Benjamin M. 
Published: June 2023

AbstractBackgroundNovel interventions that delay the onset or delay the progression of cognitive decline in older adults are extremely important, especially as the proportion of older adults steadily grows. Data on transcranial Alternating Current Stimulation (tACS) suggests it may have the potential for improving cognitive function; however, the direct implication for older adults, including those with cognitive impairment is far less understood. It is imperative to better understand the effects of tACS on cognitive function within older adults, along with treatment parameters if the therapeutic utility of tACS is to be realized.MethodFor this reason, we performed a systematic review of the literature to evaluate the effectiveness of tACS on cognitive functions within older adults. Databases were reviewed up to February 2022, which initially produced 347 unique projects. Thirty‐seven articles passed initial screening eligibility and the full texts were reviewed. Eligibility criteria included single and multiple session frequency‐specific tACS applied with the purpose of modulating cognitive performance in one or multiple cognitive domains in older adults. A total of 14 reports met the eligibility criteria and were included in the review, consisting of 294 older adults receiving tACS.ResultThe systematic review revealed that tACS show improvement in cognitive function for cognitively intact older adults (n = 5), those with mild cognitive impairment (n = 3), multi‐etiological dementia (n = 3), and Parkinson’s (n = 2), whereas 2 Alzheimer’s reports and 1 healthy aging report found no improvements. Gamma (n = 7) and Theta (n = 6) frequencies were largely targeted and showed modulations in memory, executive functioning, working memory, and gross cognitive screening measures.ConclusionDiscussion will focus on the impact of various stimulation parameters and experimental methods since significant heterogeneity in these factors indicates the need for greater standardization. In summary, tACS appears beneficial across the ADRD continuum but the intentional mapping of parameter space and standardized outcomes will be vital for future translational efforts.
Neuroprotective Effect of Perillyl alcohol in Experimental Sporadic Alzheimer’s disease
Authors: Sharma Rupali 
Published: June 2023

AbstractBackgroundAlzheimer’s is most common neurodegenerative disorder characterized by memory loss due to accumulation of amyloid‐ β fibrils. There are different pathologies that count for AD like neuro‐inflammation. This study highlights the role of oxidative stress and inflammation in progression of AD whereas Perillyl alcohol (POH) shows ant oxidative & anti‐inflammatory properties.Method54 Sprague Dawley ICV‐STZ (3mg/kg) rats (250‐300g, 7‐8 weeks) were treated with three different doses of Perillyl alcohol (25, 50 and 100mg/kg p.o.) for 13 days from 15th to 27th day. Weight measured on 1st and 28th day. Behavioral analysis had done using OFT and MWM.ResultPerillyl alcohol treatment significantly attenuates declined body weight in ICV‐STZ induced dementia in rats, showed significant increase in crossing number, and active time. Dementia induced rats were unable to discriminate familiar and novel objects, which is improved by POH. POH attenuates STZ induced acquisition deficits and retention time, increased MDA and nitrite levels. POH attenuated depleted levels of GSH, Catalase, SOD comparable to standard drug donepezil, POH decreased AChE levels in cortex and hippocampus.ConclusionStudy outcomes demonstrate neuroprotective potential of Perillyl alcohol against ICV‐STZ administration of streptozotocin induced behavioural and biochemical abnormalities. Biventricular STZ infusion produced significant impairment in learning, memory, cholinergic hypo function and elevation in hippocampal oxidative stress in rats. Rats showed poor learning, memory and unable to discriminate between familiar & novel objects in MWM and ORT. POH administration significantly attenuated STZ induced biochemical consequences. Observed beneficial effects of POH include restored cholinergic functions and antioxidant mechanisms.
The dynamic functional role of triggering receptor expressed on myeloid cells 2 (TREM2) assessed with cerebrospinal fluid and positron emission tomography measures
Authors: Crook Harry , Wahdan Malak , Edison Paul 
Published: June 2023

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) regulates several microglial activities and is essential for microglia to switch to an activated state. The role of TREM2 in the pathogenesis of Alzheimer’s disease (AD) is unclear, however. Following its role in microglial activity, the ectodomain of TREM2 is cleaved into the soluble proteolytic end product of TREM2 (sTREM2), which is released from the transmembrane domain into the cerebrospinal fluid (CSF) and, therefore, CSF sTREM2 is considered a biomarker of TREM2 activity.MethodTo examine the role of TREM2, we explored the relationships between CSF sTREM2, amyloid‐beta (Aβ42), phosphorylated tau‐181 (p‐tau‐181), and total‐tau (t‐tau) in a cohort of 495 participants (100 patients with AD, 257 patients with MCI, and 138 controls) whose data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Associations between CSF sTREM2 and 18F‐fluorodeoxyglucose (18F‐FDG) positron emission tomography (PET), 18F‐florbetapir (18F‐AV45) PET, and grey matter volume (GMV) were also investigated.ResultCSF sTREM2 levels were stable across AD, MCI and cognitively normal subgroups. In the whole cohort, CSF sTREM2 positively correlated with age (r = 0.214,p<0.001), CSF Aβ42 (r = 0.118,p = 0.009), CSF t‐tau (r = 0.423,p<0.001), and CSF p‐tau‐181 (r = 0.396,p<0.001), and negatively correlated with MMSE score (r = ‐0.105,p = 0.019). CSF sTREM2, t‐tau and p‐tau‐181 could significantly predict CSF Aβ42 levels, while CSF sTREM2 and Aβ42 could significantly predict CSF p‐tau‐181 and t‐tau levels. Higher CSF sTREM2 was associated with greater amyloid load, decreased glucose metabolism, and reduced GMV in MCI, but not in AD, in certain brain regions.ConclusionCSF sTREM2 levels were comparable across clinical groups, and with CSF sTREM2 correlating with markers of AD and neuronal damage, we predict that changes in neuropathological processes occurring in relation to changes in CSF sTREM2 levels are a result of alterations in TREM2 function, rather than quantity. Taken together with the relationships between CSF sTREM2 and imaging findings, these results suggest that sTREM2 appears early on in the AD trajectory, probably in response to early microglial activation in MCI in response to evolving pathological processes.
Experiencing the digital working transition in participant and public involvement in dementia research during the COVID‐19 pandemic
Authors: Ulate Mauricio Molinari , Woodcock Rebeca , Smith Isabelle , van der Roest Henriëtte G. , Martin Manuel Angel Franco , Craven Michael P 
Published: June 2023

AbstractBackgroundInvolvement of patients and public in research have been disrupted by the consequences of the COVID‐19 pandemic, forcing a rapid transition from face‐to‐face meetings to digital working as an alternative to engage experts by experience. This project presents a co‐production experience of a Participant and Public Involvement (PPI) group implementing a framework in dementia research, during this transition period.MethodA PPI activity was developed with the participation of the MindTech Involvement Team (PPI group) through the entire process. A group of experienced researchers, facilitators, and contributors in PPI in dementia research, and an active PPI group during the pandemic were targeted. Three online workshops were performed, and thematic analysis was chosen for the data analysis.ResultConflicting positions were identified regarding the transition from face‐to‐face meetings to digital working by using a refine version of the ‘E‐nabling Digital Co‐production' Framework as the coding structure. Regarding e‐PPI (digital PPI), the participating groups shared two perspectives associated to the non‐geographical constraints and the more business‐like sessions. For dementia research, e‐PPI was identified to decrease the supportive and respite environment associated to face‐to‐face meetings, however, it was considered to allow the participants to attend more meetings.ConclusionThe project gives feedback on the digital working in PPI by identifying concerns and fortes of this transition, both for general PPI and in the field of dementia research. It contributes further co‐production initiatives by introducing the ‘E‐nabling Digital Co‐production' Framework as a tool to reflect on future public involvement.
Co‐designing a virtual reality social connecting space for older adults living with dementia
Authors: Flynn Aisling , Reilly Gearoid , Barry Margeurite , Brennan Attracta , Redfern Sam , Casey Dympna 
Published: June 2023

AbstractBackgroundOlder adults living with dementia often experience reduced social connectedness and must be supported to enhance or maintain their social connections. Digital technology is increasingly being used to address this area. In particular, virtual reality (VR) has shown promising benefits for sociability despite not being designed for this purpose. Research has highlighted the need to design social VR spaces which can enable multi‐user experiences to foster social connectedness. Such a design process needs to meaningfully involve older adults living with dementia and their support persons from the outset.MethodsAction research was used to co‐design a VR social connecting space for older adults living with dementia. The research aimed to explore one’s experience and perception of social connectedness and how VR may be used to help older adults living with dementia stay socially connected. Using participatory methods of data collection, older adults living with dementia and their support person had the opportunity to use a VR technology probe and participate in a series of semi‐structured interviews, group meetings and design workshops. Reflexive thematic analysis was used to analyze transcripts alongside observational field notes taken by the researcher. The findings from each phase of data collection were used to inform subsequent research activities.ResultsThe meaning and importance of social connectedness is dynamic and transient. Older adults living with dementia experience several barriers and facilitators to social connectedness and their support person often plays an important role in maintaining existing connections. VR was considered a novel and enticing technology to enhance and maintain one’s connections. Older adults living with dementia and their support person expressed preferences for shared experiences and these were translated into the virtual environment (VE). Design preferences to facilitate co‐location and co‐presence in the VE were also integrated into the social connecting space.ConclusionVR was considered an enticing technology to enhance or maintain the social connectedness of older adults living with dementia. Older adults living with dementia and their support person contributed to the design decisions which shaped the development of the social connecting space.
The rate of use of actylcholinesterase inhibitors and/or the NMDA antagonist memantine in long term care dementia patients at risk for BPSD
Authors: Posar Steven Laurence , Heiser Daniel , Reid Anita 
Published: June 2023

AbstractBackgroundAccording to the CDC, 47.8% of long‐term care residents have dementia and 98% of these residents are at risk for Behavioral and Psychological Symptoms of Dementia (BPSD). Acetylcholinesterase Inhibitors (AChEIs) and the NMDA blocker memantine separately provide improvements in cognition, function, and BPSD associated with dementia. Data indicates that treatment with an AChEI and memantine in combination would be more beneficial for cognition, function, and BPSD than either drug separately. GuideStar Eldercare (GSE), a Neuropsychiatric Behavioral service agrees that this medication combination mitigates the development and severity of BPSD. We sought baseline data on long term care residents with dementia that are on either an AChEI, memantine, or both, to establish baseline information for clinical protocol development. We conducted this study to measure the levels of compliance with the standard of care that AChEI’s and/or memantine be provided for the majority of dementia patients.MethodGSE selected four buildings that were new to our services. An audit of all residents to whom we had chart access was completed. Criteria included established dementia and AChEI and/or memantine use prior to initiation of our services. A ratio of those residents with a qualifying dementia diagnosis compared to those with AchEI and/or memantine use was calculated.ResultsData review demonstrated: Building A, Michigan‐35 residents with dementia, 8 (23%) residents on medications, and 27 (77%) not on medications. Building B, Ohio‐41 residents with dementia, 8 (20%) residents on medications, and 33 (80%) not on any medications. Building C, Indiana‐26 residents with dementia, 3 (12%) residents on medications, and 23 (88%) not on medications. Building D, Michigan‐20 residents with dementia, 8 (40%) on medications, and 12 (60%) not on medications.ConclusionOf 122 total patients, 27 were on medications (22%) and 95 were not on any medications (78%). We believe this presents opportunity to initiate AChEI and memantine as the standard of care for almost all dementia residents yielding significant improvement in their BPSD clinical status.
Why should we discuss gender inequalities in Latin America and their effects in later life?
Authors: Ribeiro Fabiana , Leist Anja K. 
Published: June 2023

AbstractBackgroundHigh inequalities in Latin America (LA) affect social groups differently, with women being disadvantaged in many domains. Further, dementia prevalence is higher and with earlier onset in LA, especially among women, after accounting for women’s longer life expectancy. This narrative review discusses the modifiable risk factors of dementia established by previous studies and postulates further harmful, often hidden, factors experienced by women that might influence gender‐specific time of onset and general prevalence of dementia.MethodWe searched databases for qualitative and quantitative articles systematising dementia‐associated factors between genders/sexes in LA.ResultWe review hidden modifiable risk factors for late‐life cognitive impairment that should be integrated into future research. In doing this, we point out pervasive gender roles around education, labour market participation, but also the distribution of resources within families and across generations. Gender roles affect family structure living conditions during childhood and extend their influence over the life course. Other stressors strongly correlated with established modifiable risk factors or intrinsically relevant to dementia risk seem to be commonplace in women’s lives in LA, such as food insecurity, overweight/obesity, violence, and limited career opportunities.ConclusionBased on the evidence of gender inequalities in many domains to the disadvantage of women in LA, there is a need to consider unexplored risk factors since they could perpetuate burden of dementia among women disproportionately. Moreover, bringing hidden risk factors to open discussion can encourage and promote public policies to decrease gender inequalities and protect women’s health and well‐being.
Sex‐specific DNA methylation differences associated with Alzheimer’s disease
Authors: Wang Lily , Silva Tiago C , Young Juan J , Zhang Lanyu , Gomez Lissette , Schmidt Michael A. , Varma Achintya , Martin Eden R. 
Published: June 2023

AbstractBackgroundSex has increasingly been recognized as an important factor contributing to the heterogeneity in Alzheimer’s disease (AD).MethodWe performed a sex‐specific meta‐analysis of two large epigenome‐wide association studies (ADNI, AIBL) in the blood, with a total of 633 and 651 samples in females and males, respecitively. For each dataset, we adjusted covariate variables age, sex, batch, and immune cell‐type proportions. The Inverse‐variance fixed‐effects meta‐analysis model was then used to prioritize the most consistent DNAm differences across datasets.ResultIn female samples, 2 CpGs, mapped to the PRRC2A and RPS8 genes, reached the 5% false discovery rate (FDR). No CpGs reached 5% FDR in male samples analysis. At a more relaxed significance threshold of P < 1×10−5, an additional 22 CpGs and 5 CpGs were identified in female samples and male samples, respectively. For these 29 AD‐associated CpGs, the odds ratios ranged from 0.843 to 1.335 in females and 0.993 to 1.058 in males. The majority of these CpGs were hypermethylated in AD subjects (23 CpGs), located outside CpG islands or shores (27 CpGs), or in distal regions located greater than 2k bp from the TSS (27 CpGs). Only 2 of these 29 CpGs were located in gene promoters at SLC5A8 and C16orf89.At 5% Sidak corrected P‐value, our DMR analysis using comb‐p software identified 49 distinct differentially methylated regions (DMRs) in female and male samples each. The median numbers of CpGs in these DMRs are 5 CpGs in females and 4 CpGs in males. Among the top 10 most significant DMRs, about half of them (6 in females, 5 in males) were hypermethylated in AD. In females, 5 out of the 10 DMRs were mapped to promoter regions of the NNAT, CCDC169‐SOHLH2, ARHGEF15, LPAR5, and ZNF595 genes. In males, 4 out of the 10 DMRs were mapped to promoter regions of the MCCC1, PM20D1, PRR19, TTC23, and LRRC28 genes.ConclusionAs sex is a strong factor underlying phenotypic variability in AD, the results of our study are particularly relevant for a better understanding AD pathophysiology. They also provide a valuable resource for sex‐specific biomarkers and drug targets in AD.