bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of amyloid and tau pathology in longitudinal cognitive reserve
Authors: Borelli Wyllians Vendramini , Schlickmann Thomas Hugentobler , Ferrari‐Souza João Pedro , de Bastiani Marco Antônio , Bieger Andrei , Schilling Lucas Porcello , Rosa‐Neto Pedro , Zimmer Eduardo R.
Published: January 2025

Background

Higher educational attainment is frequently associated with lower risk of cognitive decline. Many neuroprotective factors have been suggested as the biological underpinnings of cognitive reserve (CR), though the neural basis of CR is yet unclear. Herein, we aim at investigating the effect of CR using educational attainment in individuals stratified by amyloid and tau status.

Method

A total of 135 participants, classified as cognitively unimpaired (CU) or Mild Cognitively Impaired (MCI), were selected from the ADNI cohort. All individuals that presented longitudinal measures and available amyloid and tau PET at baseline were included in this study. Formal years of education were selected as a proxy of cognitive reserve in this study, and individuals were classified into high CR (>17 years of education), intermediate CR (between 17 and 16), and low CR (<16 years of education) based on interquartile range. This analysis was in accordance with the most recent research framework to identify the mechanisms of cognitive reserve. A linear mixed‐effect model was performed to evaluate the interaction of cognitive reserve in the relationship between cognitive decline and AT status. The model was adjusted for age, sex, baseline diagnosis. Data is presented in mean±SD.

Result

A total of 58 high CR (71.7±5, 57% males), 41 intermediate CR (70.4±6, 59% males) and 36 low CR (69.8±6.4% males) were included (Table). At baseline, these individuals were divided as A‐T‐ (n=69), A‐T+ (n=11), A+T‐ (n=27) and A+T+ (n=28). Mean follow‐up time of the sample was 3.15±0.9 years. Linear mixed‐effect model showed a significant interaction of cognitive reserve in the relationship between CDR‐SOB and A+T+ status (beta = 0.24, p‐val = 0.019), after adjusting for covariates. Sensitivity analysis adjusting for APOE status also demonstrated the same relationship.

Conclusion

The neuroprotective effect of cognitive reserve was prominent in individuals with both amyloid and tau pathology, but not in the Alzheimer's pathological changes (A+T‐). Understanding the neural basis of cognitive reserve may greatly improve the advancements in therapeutic targets for secondary prevention of cognitive decline in individuals with identified Alzheimer's disease pathology.
Plasma NfL, ptau181 and GFAP as potential biomarkers for neuropsychiatric symptoms and related long‐term outcomes in a memory clinic cohort
Authors: Rabl Miriam , Zullo Leonardo , von Gunten Armin , Popp Julius
Published: January 2025

Background

Neuropsychiatric symptoms (NPS) are common in older people, may occur early in developing dementia, and have been associated with worse long‐term outcomes. The objectives here were to investigate whether plasma neurofilament light chain (NfL), tau phosphorylated at threonine 181 (ptau181), and glial fibrillary acid protein (GFAP) are associated with a) current NPS, b) future NPS, c) NPS severity change and d) cognitive and functional decline over time. And whether the presence of NPS combined with plasma biomarkers are useful to predict these long‐term outcomes (b‐d).

Method

151 participants with normal cognition (n=67) or cognitive impairment (mild cognitive impairment and mild dementia, n=84) were examined in a longitudinal memory clinic study. Plasma NfL, ptau181 and GFAP were measured at baseline. NPS were assessed through the Neuropsychiatric Inventory Questionnaire (NPI‐Q) at baseline and follow‐up, while cognitive and functional decline was evaluated trough the Clinical Dementia Rating – sum of boxes (CDR‐SB) score (mean: 22 months). Linear regression and ROC analysis were used to address the associations of interest.

Result

Cross‐sectionally none of the three plasma biomarkers was associated with NPS after adjusting for age, sex and cognitive impairment. Higher NfL was related to NPS at follow‐up (β = 0.24, 95% CI 0.04‐0.45, p = .022). NfL (β = 0.22, 95% CI 0.00‐0.44, p = .047) and GFAP (β = 0.26, 95% CI 0.05‐0.48, p = .017) were associated with an increase in the NPI‐Q severity at follow‐up. Furthermore, both markers were associated with increase in the CDR‐SB score (NfL: β = 0.29, 95% CI 0.06‐0.52, p = .013; GFAP: β = 0.33, 95% CI 0.11‐0.56, p = .004). Adding NPS and all three plasma biomarkers to a reference model improved the prediction of future NPS (AUC 0.75 to 0.84, p = .015) and cognitive decline (AUC 0.87 to 0.95, p = .030) but not the change in the NPI‐Q severity (AUC 0.67 to 0.71, p = .264) over time.

Conclusion

NfL and GFAP are associated with NPS and related long‐term outcomes. Considering the presence of NPS along with blood‐based biomarkers may improve prediction of clinical progression in memory clinic patients and improve clinical decision making.
Association between markers of brain pathology and verbal memory binding in autosomal dominant Alzheimer’s disease
Authors: Parra‐Rodriguez Mario A , Baena Ana Y , Munera Diana , Badillo‐Cabrera Alex L , Félix Nikole A Bonillas , Lopera Francisco , Quiroz Yakeel T.
Published: January 2025

Background

There is a need to develop neuropsychological measures to detect Alzheimer’s disease (AD)‐pathology and track cognitive changes along the AD trajectory. We previously showed that memory decline during word list learning (CERAD), associative memory (LAS‐FNAME test), working memory (Visual Short‐Memory Binding Test), and others, are associated with amyloid and tau pathology in members of Colombian families with autosomal dominant AD. Here we sought to determine whether associative verbal memory (Memory Binding Test ‐ MBT, (Buschke, 2014)) is associated with PET in vivo markers of brain pathology and whether it can distinguish those who will develop dementia later in life due to autosomal‐dominant AD from age‐matched non‐carriers.

Methods

A total of 33 PSEN1‐E280A carriers (Age=37.6±6.17; 61% females) and 37 non‐carriers (Age=35.1±5.87; 54% females) from the Colombia‐Boston (COLBOS) Biomarker study were included. They were matched according to age and education. All participants completed cognitive testing, florbetapir (amyloid), and flortaucipir (tau) PET imaging. We implemented regression models to investigate the extent to which group membership, cortical amyloid burden, and regional tau pathology accounted for performance on the MBT.

Results

Carriers showed poorer performance on the MMSE (p<0.001) and higher scores on the daily living functions scale (FAST, p<0.001), suggesting they were in the early symptomatic stages. Performance on the MBT was significantly accounted for by group membership (R2=15.7%, p < 0.001) whereby carriers of the mutation exhibited significant deficits (p<0.001). Aβ and Tau pathology also accounted for performance on the MBT with the best model retaining cortical Aβ and Tau in the precuneus (R2=54.7%, p < 0.001). Controlling for disease severity (MMSE and FAST), but not for age or education, removed the above effects.

Conclusions

Associative memory (i.e., MBT) is sensitive to AD‐related brain pathology in the early stages of ADAD due to PSEN1‐E280A. These current findings, together with those reported previously, suggest that the early stages of the ADAD continuum can be traced with sensitive memory tests.
Principal Component Analysis discriminates lipid metabolites in the plasma of individuals with MCI, Alzheimer's, and Down Syndrome
Authors: Sarno Tamires Alves , Pereira Cícero Augusto Costa , Talib Leda Leme , Gattaz Wagner Farid , Forlenza Orestes Vicente
Published: January 2025

Background

There is evidence indicating that disruptions in lipid metabolism are implicated in the pathophysiology of Alzheimer's disease (AD), with systemic repercussions that can be identified in peripheral blood. Recent studies conducted by our group have identified abnormalities in lipid metabolism among patients with mild cognitive impairment (MCI) and dementia (probable AD), through the investigation of a specific panel of lipid metabolites in plasma. Although much remains to be elucidated about the complex interaction between disturbances in lipid metabolites and the pathogenesis of AD, this promising research area offers exciting opportunities for the development of new strategies for disease diagnosis, treatment, and prevention.

Method

Blood plasma samples were collected from the following groups: individuals with Alzheimer's disease (AD, n=17), individuals with Mild Cognitive Impairment (MCI) showing pathological AD signature (n=17), individuals with MCI without pathological AD signature (n=17), individuals with Down syndrome (n=17), elderly (n=17), and young (n=17) cognitively healthy individuals. We used liquid chromatography coupled with mass spectrometry (LC‐MS/MS) for lipidomic analysis.

Result

A total of 29 lipids were identified by principal component analysis (PCA) from a dataset consisting of 208 lipids. The lipid modules (attached image) composed of lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and sphingomyelin are differentially expressed in the samples. PCA1 (74.92%) and PCA2 (27.6%) account for the majority of variance in the sample (attached table).

Conclusion

Our preliminary findings suggest that the use of PCA analysis may aid in discriminating differently expressed lipids in the plasma of individuals with dementia syndromes
A novel fMRI memory paradigm designed for brain imaging studies in early Alzheimer’s Disease
Authors: Joshi Himanshu , PT Sivakumar , Venkatasubramanian Ganesan , John John P , Thompson Paul M.
Published: January 2025

Background

We present the results of a task‐based fMRI study in early Alzheimer’s disease (mild cognitive impairment, MCI and mild Alzheimer’s disease, AD) using a novel‐fMRI memory paradigm suitable for use in patients with significant cognitive impairment having difficulties with remembering complex instructions.

Method

The study samples comprised 65 patients with early AD(MCI n = 42; 21 males; mild AD n = 23; 16 males) and 26(14 males) elderly cognitively healthy control(eCHC) participants. The incidental encoding phase of the paradigm (7 minutes) comprised 110 trials of common objects (55 living and 55 non‐living trials which included 4 objects repeated 6 times each and 1 object repeated 5 times) while the intentional retrieval phase of the paradigm (7 minutes) comprised 55 trials of the 5 objects encoded during the previous phase(repeated 11 times each), and 55 new objects. Task‐based fMRI acquisitions were performed on a Philips Ingenia 3‐T MRI scannerand data was analysed using FEAT(FMRI Expert Analysis Tool) correcting for age, gender, education, and total brain volume.

Result

Significantly increased activations spread across bilateral fronto‐parietal and occipital cortices were noted during incidental encoding of both ‘living’ and ‘non‐living’ stimuli in MCI when compared to eCHC and in mild AD when compared to MCI. However, reduced activations spread across bilateral central and parietal opercular cortices as well as frontal, temporal and parietal brain regions were noted during the intentional retrieval phase in response to both ‘memory’ and ‘non‐memory’ stimuli in MCI when compared to eCHC and in mild AD when compared to MCI.

Conclusion

The increased brain activations of brain regions involved in during the incidental encoding phase reflects effortful encoding of novel stimuli in patients with early AD. The brain regions that showed reduced activations during the intentional retrieval phase have been previously reported to be involved in various processes that underlie retrieval of previously encoded memory traces. The results of the study support the utility of this novel‐fMRI memory paradigm as a tool suitable for brain imaging research in cognitively impaired research participants.
RESISTANCE EXERCISE AND BRAIN CONNECTOME IN MILD COGNITIVE IMPAIRMENT
Authors: Ribeiro Isadora Cristina , de Campos Brunno , Teixeira Camila Vieira de Ligo , Uchida Marco Carlos , Aventurato Ítalo Karmann , da SIlva Marjorie Cristina Rocha , Gonçalves Brenda Costa , Rizzi Liara , Rochetti Ana Luiza Gonçalves , Guimaraes Emanuel R. , Magalhães Thamires Naela Cardoso , Fernandes Paula , Balthazar Marcio Luiz Figueredo
Published: January 2025

Background

Individuals with Mild Cognitive Impairment (MCI) are at greater risk of developing Alzheimer's disease (AD). Previous studies have shown that physical exercise is a protective factor against the clinical evolution of dementia in MCI. Lower muscle strength levels are associated with a greater risk of AD incidence. Physical exercises can also promote improvements in brain networks' functional connectivity (FC). However, the influence of resistance exercise, which significantly impacts the development of muscular strength and cognition, remains unknown concerning FC in MCI. We aimed to investigate the FC of brain networks after 24 weeks of resistance training.

Method

37 older adults with MCI were investigated. Nineteen performed the resistance training protocol, and 18 constituted the control group, not performing the exercises. Participants were evaluated before and after the intervention using a magnetic resonance imaging device (3 Tesla) for functional magnetic resonance imaging. FC was assessed in Matlab software using the uf2c program to investigate intra‐network connectivity, considering a p‐value of 0.05 with an FDR‐corrected comparison. We evaluated 12 networks: AnteSalience, PostSalience, Auditory, BasalGanglia, Dorsal Default Mode Network, Ventral Default Mode Network, Language, Left executive control network, Right executive control network, Sensorimotor, Visual and Visuospatial networks.

Result

AnteSalience connectivity decreased in the control group (T‐score > 3.1473) and increased in the exercise group in the PostSalience (T‐score > 3.7114). The results suggest that the training intervention also increased the FC of the visuospatial network (uncorrected results T‐score > 2.7195), while the control group showed no changes. None of the other networks shows differences between the pre‐and post‐intervention moments. The intervention time may have influenced the results, as changes in FC tend to occur over extended periods; even so, resistance exercise proved influential.

Conclusion

FC increased or tended to increase in some networks in the exercise intervention group, while in the control group, it decreased or remained stable, suggesting that exercise may be a beneficial modulator of brain connectivity in specific networks such as AnteSalience, PostSalience, and the Visuospatial network. More studies are suggested, especially those that monitor FC changes over extended periods.
Plasma proteomic changes in carriers of progranulin mutations on the novel NULISA platform
Authors: Simrén Joel , Benedet Andrea L. , Zhang Bingqing , Molfetta Guglielmo Di , Cantoni Valentina , Libri Ilenia , Rivolta Jasmine , Blennow Kaj , Zetterberg Henrik , Borroni Barbara , Ashton Nicholas J.
Published: January 2025

Background

With no effective therapy targeting the pathology of genetic frontotemporal lobar degeneration (FTLD), there is a need for easily accessible biomarkers enabling the development of therapeutic agents and for clinical diagnostics. Thus, we aimed to investigate the proteomic changes in plasma of progranulin (GRN) mutation carriers using a novel ultrasensitive antibody‐based platform.

Methods

We cross‐sectionally evaluated carriers of pathogenic GRN mutations (GRN+) and age‐ and sex‐matched cognitively healthy non‐carriers (GRN‐) from the University of Brescia. Participants underwent venipuncture, with blood being collected in EDTA tubes to obtain plasma. In these samples, we quantified the proteins included in the “CNS disease panel” on the novel nucleic acid‐linked immuno‐sandwich assay (NULISA) platform (Alamar Biosciences). Biomarker data were log2‐transformed prior to statistical analysis, including linear models (age and sex as covariates) comparing protein concentrations between GRN+ and GRN‐. P‐values were adjusted for false discovery rate (FDR). Protein log2‐fold changes between GRN+ and GRN‐ were calculated using untransformed data.

Results

We included twenty (2 presymptomatic and 18 symptomatic with median [range] Global CDR plus NACC FTLD scores of 1 [0.5‐3]) GRN+ and twenty GRN‐ (median [range] age 64 [45‐85] years, 65% women). Fifty‐four of the 116 proteins quantified had an adjusted P<0.05 (Figure 1). Significantly altered proteins included markers of neuronal/synaptic injury (neurofilament light [NfL], α‐synuclein, tau, NPTX2 and SNAP‐25, log2‐fold changes 0.2‐2.7; Figure 2A‐E), glial activation/neuroinflammation (glial fibrillary acidic protein [GFAp], YKL‐40, MDH1, FABP3, and sTREM2, log2‐fold changes 0.5‐1.5; Figure 2F‐J) and blood‐brain barrier dysfunction (PDGFR‐β and VEGFA, log2‐fold changes 0.6 and 0.8; Figure 2K‐L). Notably, TDP‐43 was elevated in GRN+ (log2‐fold change 1.5, P<0.01; Figure 2M). Notable markers that were unaltered included p‐tau217, Aβ42 and NPTX1.

Conclusion

Using a biomarker panel simultaneously quantifying >100 relevant proteins on the NULISA platform, clear plasma proteomic alterations were observed in GRN mutation carriers. This new methodology has the potential of improving clinical diagnostics and trials, as well as providing insights into the pathophysiology of FTLD due to GRN mutations. Further data will increase the sample size, including >20 presymptomatic carriers, C9orf72 mutation carriers, and a wider range of disease phenotypes, providing opportunities for more detailed analyses.
Acute treatment with OLX‐07010 reduced tau aggregates and upregulated a marker of autophagy with dose dependence in aged P301L tau JNPL3 mice
Authors: Patel Dhruv R. , Lopez Patricia , Romero Daisy , Davidowitz Eliot J. , Moe James G
Published: January 2025

Background

OLX‐07010 is an oral small molecule inhibitor of tau self‐association that prevented the accumulation of tau aggregates in the htau mouse model expressing wild type human CNS tau isoforms and in P301L tau JNPL3 mice using chronic treatment by administration in diet (Davidowitz et al., 2020, PMID: 31771053; 2023 PMID:37556474). A therapeutic study of JNPL3 mice with chronic treatment from 7‐12 months of age inhibited the progression of tau aggregation and improved motor coordination. This study evaluated the effect of acute treatment of aged JNPL3 mice using once daily oral dosing of OLX‐07010 for one month.

Method

Serum and brain exposure of OLX‐07010 was determined following a single oral dose via gavage to select the optimal doses for the short‐term treatment study. This study was designed with four groups: Baseline (7 months; n = 15), Vehicle (n = 20) and two treatment groups (20 and 40 mg/kg; n = 20 each). Treatment was administered from nine to ten months‐of‐age once daily by oral gavage. Cortical levels of aggregated tau were determined by two independent methods, SDS‐PAGE to resolve aggregates with immunoblot for detection, and high‐speed centrifugation to pellet aggregates with AlphaLISA for detection. Cortical levels of LC3‐II protein were evaluated using immunoblot. Motor behavior was evaluated from 7‐10 months of age using Open Field Test and Rotarod assays. The primary endpoint was reduction of aggregated tau with statistical significance; secondary endpoints included dose‐dependent reduction of tau aggregation and rescue of motor impairment.

Result

This work characterized the exposure of orally dosed OLX‐07010 in the blood and brain and demonstrated a dose‐dependent reduction of tau aggregates to baseline levels in conjunction with a dose‐dependent increase of LC3‐II, a marker for autophagosome levels, in the cortex and amelioration of the motor impairment phenotype in aged JNPL3 mice, all with statistical significance.

Conclusion

Four weeks of daily oral dosing was sufficient to demonstrate a dose dependent therapeutic effect on tau pathology and motor function supporting clinical development of OLX‐07010. This molecule, selected for inhibiting tau self‐association in vitro, may also improve the clearance of protein aggregates in vivo, further supporting its therapeutic potential.
Analytical Validation of MSD S‐PLEX Neurology Panel 1
Authors: Demos Catherine , Padmanabhan Nikhil , Cohen Rachel , Brown Jermaine , Gorham Taron , McBride Jack , Sesay Sia , Valez Sol M Rivera , Barnes Allan , Yang Jun , Graham David , Everett Allen D , Mathew Anu , Stengelin Martin , Sigal George , Wohlstadter Jacob N
Published: January 2025

Background

Three blood‐based biomarkers of neurological injury—glial fibrillary acidic protein (GFAP), neurofilament light (Nf‐L), and Tau—have emerged as promising biomarkers of neurological disorders and injuries such as hypoxic‐ischemic encephalopathy (HIE), traumatic brain injury, and Alzheimer’s disease (AD). The low levels of GFAP, Nf‐L, and Tau in serum and plasma require highly sensitive assays to detect them. Here, we report the analytical validation of an ultrasensitive, electrochemiluminescence‐based, multiplexed immunoassay for neurological biomarker assessment.

Method

The MSD S‐PLEX Neurology Panel 1 kit uses ultrasensitive S‐PLEX assay technology to simultaneously measure GFAP, Nf‐L, and Tau (total) in a 96‐well plate format. Analytical validation was performed in a series of studies based in part on Clinical and Laboratory Standards Institute guidelines to evaluate precision, dilution linearity, interference screening, detection capability, stability, spike recovery, and cross reactivity. Reproducibility was performed to assess precision across three different laboratories at MSD, Johns Hopkins University, and All Children’s Hospital using three independent reagent lots and an identical sample set.

Result

In this study, the assay used 5 μL of a sample per replicate. This differs from the commercial protocol for this panel because of the extremely high concentrations observed in HIE samples. The quantifiable range of the assay was 2.4–4,200 pg/mL for GFAP, 7.6–10,000 pg/mL for Nf‐L, and 0.34–740 pg/mL for Tau. A set of 15 common interfering substances was screened, and none showed interference exceeding 18%. Dilution of spiked samples up to 256‐fold recovered at 80‐120% of the expected value for all analytes. Precision error was calculated using identical samples across 3 independent laboratories and 3 production lots of the panel (180 measurements) demonstrating excellent reproducibility. The samples included adult and umbilical cord serum and plasma, samples containing human anti‐mouse antibodies, anti‐nuclear antibodies, and clinical samples, including those from subjects with AD.

Conclusion

The MSD S‐PLEX Neurology Panel 1 kit provides a new, analytically validated tool for assessing human GFAP, Nf‐L, and Tau. The kit is sufficiently sensitive to detect these analytes in normal serum and plasma and its dynamic range is capable of quantifying elevated levels found in target neurological disorders.
Understanding Willingness to Share SBEDOH Information: Cultural Sensitivity and Community Engagement in ADRD Research
Authors: Adams Larry D. , Rajabli Farid , Douglas Mary E , Sanchez Jose Javier , Moise Rhoda , Cuccaro Michael L. , Pericak‐Vance Margaret A , Seixas Azizi A
Published: January 2025

Background

Understanding social, behavioral, and environmental determinants of health (SBEDOH) are key in identifying modifiable risk factors for Alzheimer’s Disease and related Dementias (ADRD), particularly the disproportionate burden seen in minorities. However, a lack of standardized SBEDOH methods exists with current methods limited in scope and cultural sensitivity (i.e. can be used across different settings and populations and devoid of stigma). To address these gaps, we created a SBEDOH survey and conducted focus groups in Black American (BA) and Hispanic/Latino (H/L) participants to determine the culturally sensitivity and how best to communicate the survey benefits to diverse groups.

Method

Focus groups were conducted, engaging 11 BA and 15 (H/L) individuals, using semi‐structured interviews to elicit in‐depth discussions around the cultural sensitivity of SBEDOH items (56 questions, across 13 SBEDOH domains). Sessions were transcribed verbatim, and thematic analysis performed using NVivo software. Two primary coders analyzed data, with a third coder resolving discrepancies. The semi‐structured nature of the interviews facilitated flexible dialogue, probing deeper to responses, enriching the data collected for cultural nuances.

Result

We identified nine cultural sensitivity themes: initial reactions, participation interest, impact perception of information sharing, survey benefits communication, research engagement, tangible benefits, potential misuse of shared data, emotional reactions, and attitudes towards SBEDOH. BA’s reluctance was linked to historical mistrust (e.g. slavery), while H/L’s were about privacy. Both groups noted the importance of clarity on the survey’s benefits to their communities and research at‐large. Readiness to participate was contingent upon careful consideration of these aspects to ensure cultural sensitivity and trust‐building. Both groups emphasized the expectation that information be relayed by culturally responsible professional and SBEDOH should come with guidance on available social care services, highlighting the importance of a reciprocal relationship for sharing sensitive information.

Conclusion

This study affirms that when approached with cultural sensitivity and clear communication, BA and H/L individuals are receptive to sharing SBEDOH information. The significance of culturally attuned methods and articulation of direct community benefits are critical to success, underscoring the need for an environment that fosters connectivity and trust resulting in enhanced participation in ADRD research.
Laugh with Me: A Case Study of Easing a Caregiver’s Burden through Music
Authors: Ray Kendra , Kaiser Marion , Mittelman Mary S
Published: January 2025

Background

In the United States, approximately 2 million caregivers of people with Alzheimer’s disease or related dementia (ADRD) are Latin American. As many of these caregivers are family or friends, most are not equipped with the tools necessary to address common behaviors associated with ADRD. Music‐based interventions are an effective and accessible tool to assist caregivers in addressing these persistent behaviors. Here, we provide an example of a Latina caregiver for her mother who used music to help relieve symptoms of ADRD.

Method

Carmen (pseudonym) attended a 6‐week music‐based, psychoeducational intervention explicitly created for caregivers of people with ADRD via Zoom for 1 hour. She incorporated music specific to her culture with songs like “Metete Teté” during the six weeks. The Neuropsychiatric Inventory (NPI‐Q) and Short‐Form Zarit Burden Interview were completed at pretest and posttest. A rewrite of “Stand by Me” occurred in week six. A comparison of scores was documented, and then a percentage was calculated to determine changes between the pretest and posttest. Informed by grounded theory, a lyric analysis of the rewrite of “Stand by Me” involved creating codes for each textual idea, which led to developing categories. Themes were then revealed based on the organization of codes and categories.

Result

Carmen’s burden decreased by 47% between pretest and posttest. Comparatively, there was a 77% decrease in the severity of persistent behaviors in her mom. Additionally, Carmen’s distress was reduced by 87% following the 6‐week intervention. Carmen reported that agitation remained at posttest, which contributed to mild caregiver distress. In her rewrite of the lyrics, Carmen retitled the song, “Laugh with Me.” Four themes revealed include ‘changes in the environment during sunset’, ‘agitation appears’, ‘no stress, no fear’, ‘laughter, and togetherness as the solution’.

Conclusion

This case example demonstrated the use of a music‐based intervention facilitated by a Latina caregiver, resulting in reductions in caregiver burden, caregiver distress, and neuropsychiatric symptoms in her mom. Using a case example allowed a closer analysis of NPI‐Q posttest scores, which revealed ongoing agitation. Comparatively, the lyric analysis described how agitation arises and potential caregiving techniques used to resolve agitation.
Estimating age at Aβ onset in the 1946 British birth cohort: exploring the influence of APOE ɛ4 carriership and sex
Authors: Coath William , Betthauser Tobey J. , Teague Jordan P , Scott Catherine J , Thomas David L , Dickson John , Markiewicz Pawel J , Barkhof Frederik , Schöll Michael , Richards Marcus , Fox Nick C , Cash David M , Schott Jonathan M ,   the Insight 46 team
Published: January 2025

Background

Cerebral Aβ accumulates decades before symptom onset in AD. Sampled iterative local approximation (SILA, Betthauser et al. 2022) is a technique for estimating time from Aβ positivity (Aβ+) using Aβ‐PET. Here we explore the influence of APOE‐ɛ4 carriership and sex on estimated age of Aβ+ (EAAβ) in primarily cognitively normal individuals from the longest‐running British birth cohort.

Method

Participants in Insight 46 were drawn from the 1946 British birth cohort and underwent combined PET/MR scanning with [18F]florbetapir at two timepoints. Centiloid (CL) values were calculated using a whole cerebellum reference region and partial volume correction. We used Gaussian mixture modelling (99th percentile of lower distribution) to define an Aβ+ threshold of 12 CL. We constructed a CL vs Aβ time curve with SILA from available longitudinal Aβ‐PET scans (n=324, interval=2.4+/‐0.2yrs), which was applied to the whole sample (n=463) to calculate EAAβ. Some scans were below the CL range that could be modelled, and the estimated EAAβ was truncated to the furthest time before onset on the CL vs time curve. Kaplan‐Meyer plots and Cox regression were used to investigate EAAβ and risk of estimated Aβ+ by APOE‐ɛ4 and sex, right censoring participants where EAAβ was truncated.

Result

Mean (SD) chronological age was 70.6+/‐0.7yrs at baseline and 73.0+/‐0.6yrs at follow‐up scan and 30.5% were Aβ+ve by follow‐up (n=141, 55.3% APOE‐ɛ4, 51.8% female). SILA results and distribution of EAAβ are shown in Figures 1 and 2. EAAβ were truncated due to low Aβ binding in 35.7% (n=166, 15.7% APOE‐ɛ4, 50% female). APOE ɛ4 carriers reached median EAAβ 8.6 years earlier than non‐carriers (Figure 3A). Median EAAβ for females was marginally earlier than males with overlapping CIs (Figure 3B). APOE‐ɛ4 was strongly associated with risk of estimated Aβ+ (HR[95%CI] = 2.4[1.9,3.0]), adjusted for sex. Female sex (1.1[0.8,1.3]) and the interaction between APOE‐ɛ4 and sex (1.2[0.8,1.9]) were non‐significant.

Conclusion

Estimated Aβ positivity was reached on average 8.6 years earlier for APOE ɛ4 carriers. Consistent with results from other cohorts, APOE‐ɛ4, not sex, significantly heightened the risk of estimated Aβ positivity. Future research will explore life course and downstream events related to Aβ timing.
MCI Diagnosis and Neighborhood Disadvantage Predict Differences in White Matter Microstructure in a Rural Aging Cohort
Authors: Bender Andrew R. , Giriprakash Pavithran Pattiam , Cordes Dietmar , Zhuang Xiaowei , Caldwell Jessica ZK , Miller Justin B
Published: January 2025

Background

Diffusion magnetic resonance imaging (dMRI) studies show cerebral white matter alterations are associated with both mild cognitive impairment (MCI) and contextual psychosocial factors. However, these reports are almost exclusively based on older adults residing in metropolitan areas. Individuals living in rural communities face increased risk for Alzheimer’s disease and related dementias, but little is known regarding the sensitivity of dMRI markers to incident MCI or psychosocial stressors in this population. In a rural‐dwelling community cohort of older adults, this study evaluated associations between dMRI measures of white matter microstructure and both clinical MCI diagnosis and neighborhood disadvantage.

Method

The study sample included rural‐dwelling older adults (n=69) from the Nevada Exploratory Alzheimer’s Disease Research Center. Participants were characterized as cognitively unimpaired (CU; n=42) or diagnosed with MCI (n=27) based on clinical expert consensus, and all had dMRI data and Area Deprivation Index (ADI) measures of neighborhood disadvantage. dMRI data processing leveraged the MRtrix3 fixel‐based analysis framework and free water mapping to estimate voxel‐based measures of white matter organization, transformed to a sample template. Data analysis utilized voxel‐based analysis (VBA) to model differences in clinical diagnosis and ADI scores as predictors of fiber density, crossing fiber entropy, and extracellular free water, and free water‐corrected diffusion tensor parameters, accounting for differences in age, sex, and handedness.

Results

The VBA models showed both MCI diagnosis and elevated neighborhood disadvantage predicted significantly greater (familywise error corrected p<.05) free water and reduced crossing fiber entropy in centrum semiovale and internal capsule (Figure 1). Uncorrected models for both diagnosis and higher ADI level revealed widespread associations with dMRI measures of free water, tensor parameters, and fiber density that were nonsignificant following permutation‐based corrections.

Conclusion

These preliminary findings reveal white matter alterations associated with consensus MCI diagnosis and to socioeconomic differences in a clinical cohort of rural‐dwelling older adults. The present results highlight the value of modeling extracellular cerebral spinal fluid or ‘free water’ as a marker of microstructural changes associated with both cognitive impairment and contextual psychosocial factors. Future efforts are needed to compare these effects between rural‐ and metropolitan‐dwelling older adults at risk for dementia.
EEG Alpha Rhythm Abnormalities During the Transition from Wakefulness to Light Sleep in Patients with Mild Cognitive Impairment Due to Neurodegenerative Diseases
Authors: Carpi Matteo , Salamone Enrico Michele , Jakhar Dharmendra , Lizio Roberta , Noce Giuseppe , Lopez Susanna , Güntekin Bahar , Yener Görsev , Taylor John‐Paul , Arnaldi Dario , Percio Claudio Del , Babiloni Claudio
Published: January 2025

Background

Vigilance and sleep disturbances in Alzheimer’s and related diseases, even at the stage of mild cognitive impairment (MCI), have been extensively documented, showing abnormal daytime naps and alterations in the sleep‐wake cycle. However, the EEG correlates of the transition from wakefulness to light sleep have not yet been compared between MCI patients due to Alzheimer’s vs. other neurodegenerative diseases. Therefore, it is unclear whether there are specific features of these correlates in Alzheimer’s disease (AD) patients. This issue was investigated in the present study for the first time.

Method

Data were analyzed from an international database (https://www.pdwaves.eu/) comprising neuropsychological tests, long resting‐state EEG recordings, cerebrospinal fluid biomarkers, and MRI. For this study, 18 ADMCI patients, 9 NOADMCI patients, and 11 age‐ and sex‐matched healthy (Nold) participants showing transitions from wakefulness to light sleep during the EEG recording were selected based on the evaluation of two researchers blinded to the diagnoses. EEG periods were classified into four classes according to Hori et al.’s criteria: eyes open, eyes closed, EEG flattening, and EEG ripples (the last two representing drowsiness/light sleep stages). Individual alpha frequency peak (IAF) was obtained and used to determine EEG delta, theta, and alpha (1, 2, and 3) bands. Regional EEG cortical sources (Frontal, Parietal, and Occipital) were estimated using eLORETA freeware and the ratio of the source current density for the eyes closed and ripples conditions (EC/R) was considered as the EEG correlate of sleep‐wake transitions.

Result

Participants’ characteristics are reported in Table 1. The ANOVA showed a 2‐way interaction between Group and Band (p<.001), unveiling reduced EC/R source activity in the alpha 2 (p‐values<.001) and alpha 3 (p‐values<.001) bands in the ADMCI and NOADMCI groups (Figure 1). No differences in EEG source activity were found between the ADMCI and NOADMCI groups (p>.05).

Conclusion

The preliminary results of the present study showed widespread abnormalities in the cortical neurophysiological mechanisms oscillating at alpha frequencies in patients with Alzheimer’s and related diseases at the stage of MCI, but no differences between Alzheimer’s and non‐Alzheimer’s diseases. Future studies should cross‐validate these findings with larger clinical populations and test their relationship with night sleep disorders.
Associations between plasma biomarkers and brain amyloid and tau pathologies in a population‐based cohort without evidence of cognitive impairment
Authors: Dresse Menayit Tamrat , Ferreira Pamela C.L. , Bellaver Bruna , Zeng Xuemei , Sehrawat Anuradha , Chen Yijun , Povala Guilherme , Lafferty Tara K , Villemagne Victor L , Kamboh M. Ilyas , Cohen Ann D , Klunk William E , Pascoal Tharick A. , Ganguli Mary , Shaaban C. Elizabeth , Snitz Beth E. , Karikari Thomas K
Published: January 2025

Background

Plasma biomarkers have been widely evaluated as surrogate markers for brain Alzheimer’s disease (AD) pathology. However, studies in diverse populations with lower socioeconomic status (SES) are limited. We evaluated associations between different plasma biomarkers and brain amyloid beta (Aβ) and tau positron emission tomography (PET) in a longitudinal cohort of cognitively normal participants from a medically‐ and economically‐underserved Rust Belt region of Western Pennsylvania, USA.

Method

We measured plasma Aβ42/40, p‐tau181, p‐tau231, p‐tau217, NfL, and GFAP at baseline (n=111) and in a subset (n=65) at two‐year follow‐up in the MYHAT‐NI cohort. Aβ PET and tau PET were assessed using [11C] PiB and [18F] AV‐1451, respectively, and level of functioning with Clinical Dementia Rating (CDR). We included only cognitively normal participants (CDR = 0).

Result

The baseline median age was 76.7 years; 60 (54.1%) were females, and 18 (16.2%) were APOE ε4 carriers. The follow‐up cohort had a median age of 77.7 years, with 12 (18.5%) APOE ε4 carriers and 33 females (50.8%). All plasma biomarkers showed stronger associations with Aβ PET standard uptake value ratio (SUVR) in the Aβ‐positive vs. negative participants. However, only the associations for plasma p‐tau217 (rho=0.74, P<0.001), p‐tau231 (rho=0.48, P=0.02) and Aβ42/40 (rho= ‐0.43, P=0.04) in the Aβ PET‐positive group were significant. Voxel‐wise association models of Aβ PET accounting for age, sex, and CDR showed the strongest associations in the following decreasing order for plasma p‐tau217>Aβ42/40>GFAP>p‐tau181. No significant correlation with tau PET SUVR was observed for the plasma biomarkers.

Conclusion

Plasma p‐tau217 showed the strongest association with neuroimaging measures of brain Aβ in this cognitively normal group of older adults with lower SES. These results suggest that plasma p‐tau217 might be important to screen for evidence of brain amyloidosis in cognitively normal individuals. Future work will investigate the effects of specific comorbidities and demographic factors on the outcomes and if these change over the course of the two‐year follow‐up period.
Plasma Biomarkers, Hippocampal Volume and Cognitive Effects of Oral ALZ‐801: The Phase 2 Biomarker Study and its Long‐Term Extension in APOE4 Carriers with Early Alzheimer’s Disease
Authors: Abushakra Susan , Hey John A. , Blennow Kaj , Hort Jakub , Prins Niels D. , Kesslak Patrick , Pak Winnie , Shen Larry , Zhu Xinyi , Li Caiyan , Albayrak Adem , Bracoud Luc , Suhy Joyce , Power Aidan , Tolar Martin
Published: January 2025

Background

ALZ‐801 (valiltramiprosate) is an oral inhibitor of amyloid oligomer formation in development as a disease‐modifying AD treatment, including a fully enrolled APOLLOE4 Phase 3 trial in 325 APOE4/4 homozygotes. A Phase 2 study is evaluating ALZ‐801 effects on plasma biomarkers, brain volumes and cognitive outcomes in APOE4 carriers. Plasma p‐tau181 reduction over 104 weeks is primary endpoint. A study extension includes active treatment over additional 104 weeks for a total of 208 weeks (4 years). Long term analyses include plasma p‐tau181, Aβ42/40, p‐tau217, GFAP and other emerging biomarkers. Hippocampal volume and cognition are additional outcomes.

Method

This active study enrolled 84 APOE4 carriers (MMSE ≥22; positive CSF+ biomarkers) who receive ALZ‐801 265 mg BID. CSF/plasma biomarkers were conducted at Dr. Blennow’s laboratory (Simoa, EuroImmun assays). MRIs analyzed by Clario at baseline, 52, 104, and in the long‐term extension (LTE); cognitive and biomarker tests are every 26 weeks. Biomarkers are analyzed on observed cases, hippocampal volume (HV) and cognitive tests are analyzed by MMRM with two‐sided p‐values; with Spearman’s correlations of biomarker‐clinical outcomes.

Result

Baseline mean age was 69 years, MMSE 26, 51% females, and 70% MCI; and 83 subjects had any post‐treatment efficacy assessment. Total of 75 and 70 subjects completed 52 and 104 weeks. At 104 weeks, plasma p‐tau181 reduction was 31% (p=0.045), Aβ42 reduction was 4% (p=0.042). Hippocampal volume (HV) versus untreated matched subjects from ADNI showed ∼20% less atrophy (p<0.002). Immediate and delayed memory scores (Rey test) remained at baseline levels versus 21% decline in matched ADNI subjects (p<0.0001). Memory stabilization correlated with reduced HV atrophy (r= 0.44, p=0.0002). In the 66 ongoing LTE subjects, cognitive and HV ADNI comparisons and biomarker‐cognitive correlations at 130 weeks will be reported. Most common TEAE was mild nausea, with no ARIA‐E.

Conclusion

Biomarker positive APOE4 carriers showed significant plasma p‐tau181 and Aβ42 effects, with promising HV effects that correlated with cognitive benefit. Sustained long term benefits on these outcomes over 2.5 years could support disease modification with a continued favorable safety profile of ALZ‐801. Correlations of plasma biomarkers to long‐term clinical and imaging outcomes provides valuable insights into ALZ‐801 effects in AD.
Plasma GFAP use for population enrichment of clinical trials in preclinical Alzheimer’s disease
Authors: Bellaver Bruna , Povala Guilherme , Ferreira Pamela C.L. , Bauer‐Negrini Guilherme , Lussier Firoza Z , Leffa Douglas Teixeira , Ferrari‐Souza João Pedro , Rodrigues Matheus Scarpatto , Soares Carolina , Oliveira Markley Silva , Rahmouni Nesrine , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Benedet Andrea L. , Ashton Nicholas J. , Langhough Rebecca E. , Betthauser Tobey J. , Christian Bradley T. , Wilson Rachael E , Zetterberg Henrik , Blennow Kaj , Tudorascu Dana , Zimmer Eduardo R. , Karikari Thomas K , Rosa‐Neto Pedro , Johnson Sterling C. , Pascoal Tharick Ali
Published: January 2025

Background

We showed that plasma GFAP (a proxy of astrocyte reactivity) abnormality is key to unleashing Aβ effects on tau phosphorylation in preclinical AD. This suggests that selecting cognitively unimpaired(CU) individuals with both high Aβ and plasma GFAP could offer an early time window in the disease, but with an increased risk of developing tau pathology. Here, we tested the utility of plasma GFAP for population enrichment in clinical trials focusing on CU individuals.

Method

We assessed 195 CU individuals from TRIAD (n=84) and WRAP (n=111) cohorts with plasma GFAP and Aβ‐PET at baseline and Tau‐PET ([18F]MK6240) at baseline and follow‐up. The annual rate of progression in Tau‐PET was measured as follow‐up minus baseline uptakes divided by time between scans. Aβ positivity was determined as Centiloid>20. Astrocyte reactivity positivity(Ast+) was defined based on plasma GFAP of younger Aβ‐. Effect size was calculated as the mean change in Tau‐PET divided by the SD. Estimated sample size was calculated testing a hypothesized 25%drug effect on tau accumulation reduction in the medial temporal lobe (MTL) and temporal neocortex (Neo‐T) as secondary outcomes with 80% power at a 0.05 level.

Results

A significant annual rate of MTL tau‐PET accumulation was observed in both Aβ+/Ast‐ and Aβ+/Ast+ groups (Figure 1A), while Neo‐T Tau‐accumulated only in the Aβ+/Ast+ group (Figure 1B). The Aβ+/Ast+ group has a larger effect size on Neo‐T tau accumulation (0.97) compared to Aβ+/Ast‐ (0.33) and all individuals Aβ+ (0.61; Figure 2C). Plasma GFAP as an enrichment strategy reduced the sample size of clinical trials using changes in the Neo‐T as outcome in 60% (Figure 2D), with 59% reduction in clinical trial costs (Figure 3B). Plasma GFAP as an enrichment strategy for changes in MTL tau accumulation did not provide significant advantages over using Aβ only (Figure 2‐3). Larger effect sizes in Tau‐PET accumulation were observed in WRAP than TRIAD cohort.

Conclusion

The use of Aβ+/Ast+ for population enrichment would reduce up to 59% clinical trial costs aiming to detect changes in Tau‐PET compared to using Aβ only. To conclude, clinical trials focusing on preclinical AD would benefit from enrolling individuals with both Aβ pathology and astrocyte reactivity to select individuals enhancing trial cost‐effectiveness.
The impact of obstructive sleep apnea on cognitive decline in adults with Down Syndrome – preliminary findings
Authors: Assunção Cecilio Ana Paula , Carvalho Claudia Lopes , Gonçalves Aline Souza , Hasan Rosa , Sennes Luiz Ubirajara , Forlenza Orestes Vicente
Published: January 2025

Background

Sleep‐related breathing disorders are commonly reported in the Down Syndrome (DS) population, but data on its prevalence and severity are scarce, especially for the adult population. The increase in life expectancy and premature aging in patients with DS reinforces the need for an assessment of sleep quality. This study evaluated sleep‐disordered breathing in adults with DS using sleep measures by polysomnography. The aim of this study is to define the association between the severity of obstructive sleep apnea (OSA) in adults with DS and the clinical diagnoses of stable cognition versus prodromal dementia and dementia. Furthermore, it was possible to correlate sleep respiratory variables in these groups.

Method

All participants underwent a sleep study Type 1 Polysomnography, analyzed according to the American Academy of Sleep Medicine (AASM). The diagnostic criteria for OSA and its severity were based on the description of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5). A multidisciplinary consensus including psychiatrists and geriatricians classified the participants into three diagnostic groups: stable cognition, prodromal demetia, and dementia. A neuropsychological assessment was carried out, according to the Cambridge Examination for Mental Disorders of Older People with Down’s Syndrome and Others with Intellectual Disabilities (CAMDEX‐DS). The Kruskal‐Wallis test was applied to evaluate our results.

Result

3 participants had dementia (mean AHI 17,80 events/h), 7 were classified as prodromal dementia (mean AHI 42,60 events/h) and 28 were in the stable cognition group (mean AHI 36,42 events/h). It was not possible to determine statistically significant evidence between the AHI and the diagnoses. The correlation between respiratory sleep variables demonstrated a strong association between AHI, AHI in NREM sleep and ODI values. Furthermore, the higher the AHI or ODI values, the lower the minimum oxyhemoglobin saturation. However, it was not possible to observe a correlation with the mean oxyhemoglobin saturation.

Conclusion

Studies show that OSA is the main sleep disorder in the DS population, demonstrating the importance of early diagnosis. In our analysis, it was not possible to define a correlation between OSA and clinical diagnoses, possibly because there are few non‐control cases. Being preliminary data, clinical and polysomnographic follow‐up will support our preliminary hypotheses.