bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase Ib/II Study of BXCL501 in Agitation Associated with Dementia
Authors: Risinger Robert , Rajachandran Lavanya , Robinson Heather 
Published: January 2025

AbstractBackgroundBXCL501, a sublingual film formulation of dexmedetomidine, a highly selective α2 adrenoceptor agonist, is currently being studied for the acute treatment of agitation associated with dementia.MethodThis was a Phase 1b/2 study assessing efficacy and tolerability of BXCL501 for treatment of acute agitation associated with dementia. Subjects were randomized to active treatment with BXCL501 (30, 40, or 60µg) or placebo. The main efficacy measure was PANSS Excited Component (PEC) score.ResultA total of 100 patients were enrolled in the study. Most subjects had moderate agitation at baseline based on the PEC score.At 2 hours post‐dose (primary endpoint), a significant improvement from baseline in PEC total score was observed in the 60µg group compared with placebo (LS mean difference: ‐4.2, P = 0.0011). Significant improvements from baseline in PEC total scores were also observed at 1, 4, and 8 hours. In the 40µg group, significant improvements from baseline in PEC total score compared with placebo were observed at 1, 2, and 4 hours. No significant differences from placebo were observed in the 30µg group.BXCL501 doses of 30, 40, and 60 µg were well tolerated in this patient population. None of the observed TEAEs were severe and no subjects discontinued the study due to an AE. The most frequently reported TEAE in the BXCL501 30, 40, and 60 µg treatment groups was somnolence (56.3%, 34.8%, and 60.0%, respectively); the incidence was 5.4% with placebo. Other adverse events of interest were hypotension (2 subjects each in 40µg and 60µg groups), orthostatic hypotension (one patient each in the 30 µg and 60 µg groups) and bradycardia (one patient in the 60 µg group). No cases of syncope or falls were reported in any of the groups.ConclusionThere are currently no FDA‐approved treatments for acute management of agitation in elderly patients with dementia. In this study, BXCL501 60 µg and 40 µg significantly reduced the symptoms of agitation at 2 hours after administration in this patient population, as measured by PEC. At those doses, the treatments were relatively well tolerated.
The EEG spectral power ratio as a cognitively relevant marker of preclinical AD
Authors: Fried Peter J. , Morse Christie , Northrop Andrew , Patel Rushali , McKinney Eliza L , Shah Keya , Cabral Danylo Ferreira , Buss Stephanie S. , Benwell Christopher , Ozdemir Recep , Shafi Mouhsin 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is associated with cerebral slowing on electroencephalography (EEG), or a shift in oscillatory power from higher to lower frequencies. This change can be captured as the spectral power ratio (SPR) of alpha and beta over delta and theta: (α+β)/(δ+θ). Prior studies have shown that compared to cognitively unimpaired older adults, the SPR was lower in persons with a clinical diagnosis of dementia due to probable AD and those with a biomarker‐confirmed diagnosis of amnestic mild cognitive impairment (aMCI) due to AD, and a lower SPR was associated with worse executive functions scores. Moreover, the SPR was unaffected in individuals who had amyloid‐negative aMCI, suggesting cerebral slowing may result from AD‐associated pathology. We sought to test this hypothesis in a cognitively unimpaired population using plasma Aβ42/Aβ40 levels as a surrogate biomarker of brain amyloid.MethodsEyes‐closed resting‐state EEG, neuropsychological testing, and plasma Aβ42/Aβ40 levels were obtained from 34 adults (18 women, aged 65‐89 years), as part of an ongoing study. EEG data were cleaned and analyzed using custom scripts built around EEGLAB and TESA toolboxes in Matlab. Aβ42/Aβ40 <0.1 was used as a cutoff to indicate a high risk of brain amyloid (Rissman et al., 2023, Alzheimer’s and Dementia, DOI: 10.1002/alz.13542). An executive functions composite score was created by averaging age‐normed z‐scores from the digit symbol substitution, digit span backwards, semantic fluency, verbal fluency, and trail making tests.ResultsA Shapiro‐Wilk test indicated SPR values were not normally distributed, so data were log10‐transformed. 18 participants (53%) were classified as “high‐risk of brain amyloid.” An independent‐samples t‐test showed the SPRlog10 (mean ±SD) was lower in this group (0.23 ±0.2) than those with “low‐risk of brain amyloid” (0.39 ±0.2), which was significant, t(32) = ‐2.6, p = 0.015. Pearson’s correlation coefficients showed that executive functions were significantly correlated with SPRlog10 in the high‐risk group, R(16) = 0.57, p = 0.013, but not in the low‐risk group, R(14) = 0.24, p = 0.370.ConclusionsCerebral slowing is an early feature of amyloid‐associated pathophysiology. The EEG SPR (α+β)/(δ+θ) is a sensitive and cognitively relevant marker of preclinical AD.
Large‐scale Plasma Proteomic Profiling Identifies a Robust Set of Biomarkers for Detection of Clinical Alzheimer's Disease
Authors: Heo Gyujin , Ali Muhammad , Timsina Jigyasha , Liu Menghan , Cruchaga Carlos , Sung Yun Ju 
Published: January 2025

AbstractBackgroundWhile several non‐invasive plasma biomarkers are rapidly developing, they still have lower accuracy than the established CSF biomarkers. This study therefore comprehensively examined 6,905 plasma proteins in over 3,000 individuals to identify novel biomarkers for predicting clinical Alzheimer’s disease (AD) and monitoring disease progression.MethodTo identify and validate plasma biomarkers, we performed difference abundance analysis of 6,905 plasma proteins in a total of 3,366 cases and controls from three different datasets (Knight‐ADRC discovery, Knight‐ADRC replication and Stanford ADRC). Enrichment analysis with Gene Ontology and DisGeNet were performed to understand biological significance of the identified proteins. Machine learning model was used to create prediction models for AD risk, which were replicated on the Knight ADRC replication and Stanford datasets.ResultWe identified and replicated 257 plasma proteins (including NEFL, SMOC1, SPON1, and NEUROG1) associated with clinical AD status. Machine learning model identified 89 proteins with strong prediction power for AD (AUC=0.843 in Knight ADRC; AUC=0.771 in Stanford ADRC), but not for Parkinson's disease (AUC< 0.6 in two independent datasets), frontotemporal dementia (AUC=0.726), and dementia with Lewy bodies (AUC=0.712), indicating AD specificity. This proteomic signature also predicted AD individuals with faster progression (clinical dementia rating sum‐of‐boxes changes per year; P=4.7∗10‐5). Furthermore, this model identified a subset of cognitive normal individuals at 201 times higher risk of developing AD individuals (hazard ratio =201.3; P=1.95∗10‐2). Pathway analysis highlighted proteins (APOE, SPP1, and PLTP) related to lipid transport pathways (FDR=2.7∗10‐2). DisGeNet indicated the relevance to senile cardiac amyloidosis (APOE, CRP, and NEFL; FDR=1.1∗10‐4), highlighting transthyretin, that was found to be potentially protective against amyloid beta deposition.ConclusionThis large‐scale plasma proteomic study identified proteins associated with AD, developed a robust prediction model that accurately predicted AD status, examined differences between predicted groups in progression and conversion, and revealed pathways and diseases relevant to AD. These findings from extensive analysis provides the potential of plasma proteins as biomarkers for routine clinical uses in early detection of AD and guiding AD treatment decisions. They provide valuable insights into the relevance of specific pathways and diseases in the context of AD.
Integration of a Digital Cognitive Assessment Tool in a Primary Care Setting
Authors: Doerr Adam J. , Orwig Taylor A. , Melkonyan Mark N. , Leung Robert P. , Showalter John , Jannati Ali , Purkey Sage , Mullavey Judy , Erban Stephen B. , Weinstein Bruce R. , McManus David D. , Lin Honghuang 
Published: January 2025

AbstractBackgroundAlmost all primary care providers (PCPs) believe screening for mild cognitive impairment (MCI) and dementia in older patients is important. However, there are significant barriers in primary care, including low provider confidence in their assessment skills, time constraints, competing priorities, and poor financial incentives. Consequently, PCPs report conducting cognitive assessments for less than half of patients over 60 years of age. We evaluated the feasibility of integrating Linus Health’s Core Cognitive Evaluation (CCE), a tablet‐based digital cognitive assessment, into the workflow of a primary care practice at UMass Memorial Medical Center.MethodA convenience sample was recruited from six participating PCPs’ upcoming schedules. Eligibility criteria included age >65 years, ability to read, write, and speak English or Spanish, no prior diagnosis of cognitive impairment, and no known hearing or vision impairment. Patients were contacted for inclusion by phone one month prior to their scheduled visits and were instructed to arrive at their appointments one hour early. Participants were consented in person and were asked to perform the cognitive assessment on a tablet. PCPs reviewed the report during the visit and shared the results at their discretion. A report was uploaded to each participant’s REDCap record and linked to the encounter in the electronic health record.ResultThe screened cohort consisted of 150 participants (mean age 74±6.7 years, 64% female). The CCE identified the results of 40 participants as borderline and 7 participants as indicative of cognitive impairment. Follow‐up actions taken by PCPs after positive screens included laboratory evaluations for reversible causes, referrals to neurology, and brain MRIs. As a result of taking the CCE, only 1% of patients reported feeling sad or depressed, while 5% reported feeling worried or anxious. More than two‐thirds of participants reported that taking the CCE was beneficial. All caregivers reported they would want to know if their loved ones’ brain health was declining. All PCPs reported they would continue using the CCE if made available following the study.ConclusionIntegration of the Linus CCE into a primary care setting was feasible and impacted PCPs’ clinical decision‐making, with high patient, caregiver, and provider satisfaction.
Impact of the sars‐COV2 pandemic on cognitive frailty in older adults: The role of social support
Authors: Fabbo Andrea , Manni Barbara , Villani Emanuele Rocco 
Published: January 2025

AbstractBackgroundSocial restrictions and closures of services due to COVID‐19 pandemic had a negative impact on the social inclusion and well‐being of older people. In fact, older adults present risk factors both in terms of health ‐ such as frailty or multimorbidity ‐ and in terms of quality of life ‐ for example institutionalization ‐ and poor social support. The main objective is to evaluate whether social support had the role of an effect modifier on the incidence of cognitive frailty. Material: single‐center, cohort study, based on retrospective data collected during the emergency phase of the COVID‐19 pandemic and on a re‐evaluation performed in the post‐emergency phase. To evaluate social support, Cohen’s Social Support Scale (CSSS) was used, whose higher scores identify subjects with a low level of social support. To screen for cognitive impairment, the Mini Mental State Assessment (MMSE) was used, with an adjusted score of 26 ore less indicative of cognitive impairment. Frailty was assessed through a frailty index and cognitive frailty was defined as the co‐occurence of both cognitive impairment and physical frailty.Methodspatients belonging to the frailty clinic of the Modena AUSL with a first evaluation carried out between October 2020 and June 2021 and with data relating to social support are re‐evaluated between october and December 2023.Results105 participants were enrolled. 68 (64.7%) were found to be frail at baseline. There was no statistically significant difference in mean CSSS between non‐frail and frail patients (8.7 ± 2.1 vs. 9.3 ± 2.2, p = 0.173). At December 2023, 50 patients were reevaluated. During follow‐up, 25 out of 37 patients developed cognitive frailty. The OR of cognitive frailty was higher when basal Cohen’s social support scale was higher (1.91, 95% CI 1.08‐3.25). Discussion: the impact of the pandemic, in terms of reduced social support should be assessed in the transition phase between the emergency and post‐emergency phaseConclusionsinvestments should be made to implement psychosocial support interventions to reduce further incidence of cognitive frailty among older adults
Comparing Unmet Service Needs Between Rural and Urban Family Caregivers of People Living with Alzheimer’s Disease and Related Dementias: A Multi‐Site Qualitative Study
Authors: Miyawaki Christina E. , McClellan Angela , Russell David , Bouldin Erin D. 
Published: January 2025

AbstractBackgroundThe scarcity of resources and caregiving services, a higher prevalence of health conditions, and financial concerns in rural areas in the United States have been well‐documented. However, less research has compared experiences between caregivers of people with Alzheimer’s disease and related dementias (ADRD) in rural versus urban areas. This study sought to address this gap by identifying those unmet service needs, explore factors associated with service use, and propose tailored strategies for better serving the needs of both rural and urban caregivers.MethodsUsing semi‐structured interviews guided by Andersen’s theory of health service use (1968), Taylor’s theory of dependent care (2001), and Roberto’s model of service use (2022), we interviewed 20 family caregivers of people with ADRD in rural areas of Western North Carolina and 18 caregivers within the urban setting of Houston, Texas. We compared their unmet service needs and contextual factors that facilitate their service use. We conducted a thematic analysis of interview data first with rural caregivers and developed a codebook. Using the same codebook, we analyzed the urban interview data while inductively adding new codes.ResultsRural caregivers were 56 years old (mean), working, White, and female. Urban caregivers were 63 years old, retired, White, Asian, or Black, and female. We found similar unmet service needs among rural and urban caregivers; however, the ways they approached and solved their challenges differed. Caregivers in rural areas wished for more information and caregiver support whereas urban caregivers looked for information they needed until they found the answers. Rural caregivers expressed guilt about using services because they felt they were limited and zero‐sum while urban caregivers shared available resources with others so that other caregivers could use them as well. Unmet service needs for urban caregivers included more culturally tailored services for people with ADRD in their ethnic‐specific languages and foods while rural caregivers’ cultural needs were not racially and ethnically specific but more place‐specific services.ConclusionsIncreasing options for online and virtual support groups across the United States for rural caregivers and increasing culturally tailored service options would likely increase access and use for urban ADRD caregivers.
High Frequency Oscillations in Epileptic and Non‐Epileptic Alzheimer’s Disease Patients and the Effect of Levetiracetam on the Oscillations
Authors: Chenchu Vishnu Shandilya Mungamuru , Addo‐Osafo Kwaku , Ranasinghe Kamalini G , Shamas Mohamad , Staba Richard , Nagaragan Srikantan , Vossel Keith 
Published: January 2025

AbstractBackgroundAltered network synchronization and rhythmic neural activity is observed in Alzheimer’s disease (AD). Spontaneous epileptiform activity and/or seizures occur in an estimated 60% of AD cases, and having AD increases the likelihood of seizures when compared with people without dementia. Thus, network hyperexcitability can be an early feature and helpful for diagnosis and treatment. However, it is unknown if biomarkers of epileptogenicity are detectible in AD, and if these biomarkers are affected by the anti‐seizure drug levetiracetam (LEV). One important biomarker of epileptogenicity is high‐frequency oscillations (HFOs).MethodTo measure HFOs, we used 10‐min magnetoencephalography (MEG) recordings (275‐channel, sampling rate 1200–2400 Hz) during awake resting periods in participants with AD and healthy controls. Recordings from 14 AD (6 non‐epileptic AD (NEAD, median age: 60.8, 2M/4F) and 8 having subclinical epileptic activity (EAD, median age: 54.9, 5M/3F)) and 8 control (median age: 71, 5M/3F) participants were analyzed using two software scripts: Delphos and a custom‐made script for detection of HFOs. LEV 125 mg twice‐a‐day or placebo was administered for 4 weeks in between two MEG recordings, and 4 weeks of washout before switching LEV/placebo phases for each participant.ResultHFOs were categorized into ripples (80 to 250 Hz) and fast‐ripples (250 to 500 Hz). At baseline, AD participants, including both NEAD and EAD, had higher ripple rate (RR) and higher fast‐ripple rate (FR) than controls in several regions (p<0.05, paired t‐test/ANOVA‐Tukey). Additionally, compared to EAD, NEAD had higher RR in left‐frontal, left‐temporal, and cerebral fissure regions, and higher FR in left frontal regions (p<0.05, ANOVA‐Tukey). In both EAD and NEAD, LEV increased RR in left‐temporal and bi‐parietal regions, but decreased RR in the left central region (p<0.05, paired t‐test). In both AD groups, LEV increased FR in a few regions, but it decreased FR in right temporal region in NEAD.ConclusionAD had a high level of HFOs, with higher numbers observed in non‐ epileptic AD. LEV resulted in region‐specific increases in HFOs in both NEAD and EAD. Thus, HFOs can function as a biomarker of hyperexcitability in AD; however, their contribution to the epileptic phenotype in AD requires further investigation.
Haptoglobin related protein without signal peptide induces a new syndrome of renal salt wasting in Alzheimer’s disease
Authors: Maesaka John K , Imbriano Louis J , Candace Grant , Miyawaki Nobuyuki 
Published: January 2025

AbstractBackgroundA new pathophysiologic approach to evaluating hyponatremic patients identified the different causes of hyponatremia, including non‐hyponatremic patients with renal salt wasting (RSW). RSW was considered a rare to nonexistent syndrome until we found 24 (38%) of 62 hyponatremic patients in a general medical ward to have RSW. We induced RSW in rats by injecting plasma from 18 AD patients suspected to have RSW. We utilized lithium as a marker of sodium transport in the proximal tubule. All 18 AD patients below a mini‐mental state examination (MMSE) score of 12 had increasing excretion of lithium from 33 to 58%.MethodsThe same renal clearance studies demonstrated natriuretic activity (NA) in AD serum. We subjected the serum with NA and normal control serum to proteomic analyses to identify the protein content in both sera.ResultsFractional excretion (FE) of sodium and lithium increased from 0.2% to 0.69 % and 24.4 to 52.5% in the control and AD sera, respectively. FElithium progressively increased from 33% to as high as 58% as MMSE decreased from 12 to zero. Phenotype specific haptoglobin 1‐1, and 2‐2, kininogen, thrombospondin, PROZ, alpha‐1 microglobulin/bikunin, and retinol binding protein did not have NA. Haptoglobin related protein with signal peptide did not have NA but there was a robust dose response to haptoglobin related protein without signal peptide (HPRWSP). Am Jour Med Sci 2021;361:261‐268ConclusionIt appears that every patient below an MMSE of 12 becomes progressively dehydrated. Studies are underway to determine whether HPRWSP can serve as a biomarker of RSW in Alzheimer’s disease and to determine the prevalence of RSW at different stages of dementia.
Life Review Depression Intervention Conducted by Asian and White American Caregivers: A Mixed‐Method Comparative Study
Authors: Miyawaki Christina E. , Bouldin Erin D. , McClellan Angela 
Published: January 2025

AbstractBackgroundApproximately 10% of people living with Alzheimer’s dementia (PWD) experience depression, yet behavioral interventions remain scarce. We developed an innovative depression intervention, Caregiver‐Provided Life Review (C‐PLR) based on life review therapy. The purposes of this study were to evaluate the feasibility of training family caregivers in life review skills and evaluate the impact on depressive symptoms.MethodsUsing a mixed‐method design, we trained Asian (n = 15) and White (n = 24) caregiver‐care recipient dyads. Eligible caregivers were family members who cared for PWD for ≥8 hours/week, completed caregiver training, six weekly life review sessions, and five weekly Fidelity check‐in calls with the research team. Care recipients experienced mild depression (≥5 on Geriatric Depression Scale) and dementia (≥13 on Telephone‐Montreal Cognitive Assessment). We collected pre‐ and post‐measures of care recipients’ depression (primary outcome), life satisfaction, caregivers’ burden, rewards of caregiving, and dyads’ relationship quality (secondary outcomes), and compared them using paired t‐tests. We evaluated feasibility by measuring fidelity check‐in scores to the C‐PLR training protocol during these calls.ResultsThirty‐nine dyads completed the study. Asian (mean age = 52 years old) and White (59 years old) caregivers were working, female, and in good‐excellent health. Their care recipients (Asian = 82 years old; White = 80) were female and in poor‐fair health. Both Asian and White care recipients’ depression and dyads’ relationship scores from baseline to the end of the study significantly improved (Asian = 4.1 to 2.1, p<0.001; 12.5 to 13.4, p = 0.029; White = 4.1 to 3.1, p = 0.049; 13.8 to 14.5, p = 0.044, respectively). Asian (73%) and White (75%) caregivers’ fidelity scores were similarly high (p = 0.91) and rated as good‐excellent. Qualitative interviews of both caregivers supported the sentiments of the quantitative results. Furthermore, 73% of Asian dyads conducted the C‐PLR in their native language, however, it did not appear to influence any outcomes.ConclusionsWe found a significant impact of C‐PLR on depressive symptoms in both Asian and White PWD and their dyadic relationships. Both quantitative and qualitative results supported the feasibility of the C‐PLR training and the successful completion of the intervention. This study demonstrated that the C‐PLR intervention can be added to a list of successful non‐pharmaceutical interventions.