bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectral power ratio as a measure of the EEG spectral power shift in mild cognitive impairment due to Alzheimer’s disease
Authors: Flores‐Sandoval Aimee Arely , Davila‐Perez Paula , Buss Stephanie S. , Donohoe Kevin , O'Connor Margaret , Shafi Mouhsin , Pascual‐Leone Alvaro , Benwell Christopher , Fried Peter J.
Published: December 2023

Background

Markers sensitive to brain changes at the transition from mild cognitive impairment (MCI) to dementia due to Alzheimer’s disease (AD) are needed for aiding prognosis and the selection of potential responders to novel interventional therapies. EEG markers may be advantageous due to their accessibility.

Prior research suggests that AD is associated with a shift in the brain’s oscillatory activity from higher to lower frequencies which can be captured as changes in the EEG spectral power ratio (SPR: α + β /δ + θ), a measurement associated with executive function1. The aim of the present study is to extend these findings to the prodromal stage of AD, and test the association of the SPR with amyloid burden.

Method

Data was obtained from 31 participants, including 23 aMCI (17 amyloid positive: Aβ+aMCI) and 14 CU individuals. We compared the SPRs between Aβ+aMCI and CU individuals, and tested its correlation with composite scores of executive functions, learning and memory, dementia severity, as well as amyloid load in the Aβ+aMCI group. Test‐retest reliability of the SPR was also inspected and the SPR of MCI individuals with different amyloid status was explored in hypothesis generating analyses.

Result

The SPR was significantly lower in the Aβ+aMCI group compared to the CU group (p = 0.0271) and was significantly correlated with Executive Function scores (r = 0.5634). The SPR showed excellent test‐retest reliability (rAβ+aMCI = 0.8629 and rCU = 0.9786). Logistic regression suggested that aMCI participants with a lower SPR had an increased probability of a positive amyloid PET.

Conclusion

Our results extended previous findings in AD and suggested that the SPR may be sensitive to pathophysiological changes in aMCI individuals in a cognitively meaningful manner. Further research may confirm these findings and may explore the potential of this measure to aid in the classification of aMCI individuals according to their amyloid status.

1. Benwell CSY, Davila‐Pérez P, Fried PJ, Jones RN, Travison TG, Santarnecchi E, Pascual‐Leone A, Shafi MM (2020) EEG spectral power abnormalities and their relationship with cognitive dysfunction in patients with Alzheimer’s disease and type 2 diabetes. Neurobiol Aging
85, 83‐95.
Clustering of neuropsychiatric symptoms across time in Alzheimer’s disease and Mild Cognitive Impairment
Authors: Scarfo Sara , McGeown William J , Moshfeghi Yashar
Published: December 2023

Background

Neuropsychiatric symptoms are behavioural manifestations highly prevalent along the Alzheimer’s disease (AD) continuum, including at the stage of Mild Cognitive Impairment (MCI). Although various projects have investigated the factors that underpin these symptoms, the most stable clustering pattern is still matter for debate; furthermore, to our knowledge, no study has investigated, longitudinally, how clusters might change due to development of AD pathology. Therefore, our objective is to investigate neuropsychiatric clusters over time, in a large sample of MCI and AD dementia patients.

Methods

Samples were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu), using data from the Neuropsychiatric Inventory (NPI), from the baseline assessment visit, followed up yearly until data recorded at month 72. The samples included MCI and AD dementia patients (based on ADNI’s inclusion criteria), presenting with at least one neuropsychiatric symptom at the time‐point selected. Using SPSS (Version 28), we performed a series of exploratory principal components analyses (PCA), Varimax rotation, and principal axis factor analyses (FA), comparing Promax and Direct Oblimin rotations.

Results

The best‐fitting structure was interpreted at each time‐point, based on: Eigenvalues>1, items’ loadings>0.4, scree plot patterns, minimum 40% of variance explained by the model, and independence of factors. Results from both PCA and FA indicated that a unique structure could not be identified, as factors were not stable over time; however, some symptoms tended to load on the same factors across most measurements (i.e. delusions with hallucinations; agitation with depression, anxiety and irritability; to a lesser extent elation with disinhibition; apathy with aberrant motor behaviour, sleep disturbances and appetite disorder).

Conclusions

The available evidence reveals that factors underlying the neuropsychiatric symptoms in a sample of AD and MCI patients are not consistent across the time‐points. However, some symptoms tend to co‐occur across time, with implications, for example, that an investigation into one of those symptoms should consider the presence of the other; furthermore, as clear theoretically driven factors are not distinctively identified at every time‐point, this illustrates the potential importance of sample selection (e.g., disease stage, and/or heterogeneity) on studies of neuropsychiatric symptoms.
Value of Knowing following Amyloid PET Results Disclosure in Mild Cognitive Impairment
Authors: Wang Yan A , Ren Dianxu , Roberts J. Scott , Lingler Jennifer H
Published: December 2023

Background

Personal utility is commonly cited as a rationale for Alzheimer’s disease (AD) biomarker testing. Yet, limited reports document how the value of knowing one’s AD biomarker status manifests in cognitively symptomatic patients. Emerging literature suggests two potential dimensions to the construct: a) inherent value, or “knowledge for the sake of knowledge,” and b) value of knowing as a basis for action. We describe actions taken by patients following amyloid PET results disclosure with the goal of elucidating the value of knowing AD biomarker status in cognitively symptomatic populations.

Method

We analyzed longitudinal health behavior assessments completed by patients with mild cognitive impairment who learned of being amyloid positive (n = 12), negative (n = 22), or assigned to a comparison group (n = 37). Patients were 92% non‐Hispanic white, 59% male, 73±8.61 years old with 16.25±2.49 years of education. Qualitative interviews supplemented scan group participants’ data. Both questionnaires and qualitative interviews focused on activities newly adopted to promote cognitive health or plan ahead.

Result

Over 12 months of follow‐up, all participants reported at least one behavior change from baseline. Amyloid positive patients reported the most behavior changes (mean = 4.67/14±1.83) while amyloid negative patients reported the fewest (mean = 3.72±1.58). Across groups, no significant differences were observed in changes to: lifestyle, vitamin/supplement use, stress reduction activities, cognitive stimulation, and advance directive completion. Amyloid negative participants were significantly less likely than controls to consider long‐term care insurance (63.6% vs. 89.2%; P = .025), and to endorse changes classified as “other” (36.4% vs. 64.9%; P = 0.037). After adjusting for education level, gender, and MMSE, logistic regression showed that amyloid negative patients were 74% less likely than controls to report “other” changes (OR = 0.26, 95% CI [0.08, 0.85], P = 0.025), and 78% less likely to consider long‐term care insurance (OR = 0.22, 95% CI [0.06, 0.86], P = 0.03). Qualitative analysis yielded insight into “other” activities, including changes in employment, driving, and residential status, and engagement in other non‐medical activities (pursuing bucket list activities and mending strained relationships), particularly among amyloid positive patients.

Conclusion

Value of knowing one’s amyloid status may differ by scan result and encompass a wide range of actions to enhance not only cognition but quality of life.
Beyond psychological well‐being and behavior change: Participant experience and evaluation of an AD biomarker disclosure and lifestyle counseling protocol
Authors: Erickson Claire M , Basche Kristin E , Chin Nathaniel A. , Ketchum Fred B , Clark Lindsay R.
Published: December 2023

Background

Earlier detection and improved accessibility of testing means more adults may learn their Alzheimer’s biomarker results. Incorporating feedback from individuals who have learned their results is important to improve disclosure protocols and individual outcomes.

Method

Participants (n = 97,age = 71.9±4.8) from the Wisconsin Registry for Alzheimer’s Prevention study enrolled in a disclosure study consisting of an education session, amyloid PET results disclosure, and lifestyle counseling visit. Participants reported their visit satisfaction and provided feedback for improvement. Upon study completion, participants evaluated various study procedures (e.g., understanding of the results, regret in learning result, etc.). Chi‐square analyses and response distributions were computed to compare participants with an elevated and non‐elevated amyloid result.

Result

No statistically significant differences in disclosure or lifestyle visit satisfaction were found between participants with an elevated and non‐elevated amyloid PET result. Overall, 95% of participants reported that the disclosure visit was “somewhat” or “very” useful. 70% of participants endorsed the usefulness of the lifestyle counseling visit. 100% and 81% of participants recommended we continue disclosure and lifestyle counseling visits, respectively. For the disclosure visit, both groups suggested we provide more information on the amyloid result (e.g., provide scans, risk, etc.), offer an in‐person, face‐to‐face visit, and reduce the number of questions assessing suicidal ideation. Elevated participants suggested allowing a loved one to join the visit. Feedback on the lifestyle counseling visit included more accountability check‐ins and providing a more personalized discussion. On study evaluation measures, groups differed on the reported usefulness of educational materials (χ2(2,n = 87) = 6.42,p = .04) and regret in learning results (χ2(2, n = 87) = 10.7,p = .005). While no participants regretted learning their results, elevated participants were more likely to respond “neutral” (15% vs 0%), whereas non‐elevated participants were more likely to respond “strongly disagree” (74% vs. 54%) to regretting learning their result. There were no group differences on understanding or usefulness of result.

Conclusion

We found very limited differences between elevated and non‐elevated participants on satisfaction and evaluation of learning amyloid PET results. It remains important to offer follow‐up, especially for elevated participants, who may need extra support post‐disclosure. Ultimately, most participants found the study visits worthwhile and found learning their result useful.
Tau‐PET to predict conversion from mild cognitive impairment to dementia; a head‐to‐head comparison against amyloid‐PET and MRI
Authors: Groot Colin , Smith Ruben , Collij Lyduine E. , Mastenbroek Sophie E , Stomrud Erik , Binette Alexa Pichet , Leuzy Antoine , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Strandberg Olof , Ossenkoppele Rik , Hansson Oskar
Published: December 2023

Background

In contrast to amyloid‐PET and MRI, tau‐PET imaging has not been integrated into clinical practice even though it shows a close relationship with clinical symptoms. With the present study, we aim to assess the performance of tau‐PET to predict conversion to dementia (all‐cause and AD) in individuals with mild cognitive impairment (MCI), and compare it with amyloid‐PET and MRI.

Method

We selected participants from an ongoing multicenter study (n = 408, Table 1). The following ROIs were used to define quantified thresholds for positivity using an independent cognitively unimpaired reference group: a temporal meta‐region for tau‐PET and an AD‐susceptible temporoparietal region for MRI‐based cortical thickness. For amyloid‐PET, we used the standard Centiloid mask and a published threshold of 27 Centiloids to determine positivity. We additionally performed visual reads for all imaging modalities. We used Cox proportional hazard, logistic regression, and receiver operating curve (ROC) analyses to assess the performance of amyloid‐PET (A), tau‐PET (T), and MRI (N) to predict progression from MCI to dementia over a mean follow‐up period of 2 years.

Result

Hazard ratios indicated that tau‐PET and amyloid‐PET positivity (both when assessed quantitatively and using visual reads) conveyed a greater risk of progression to dementia than MRI, and that a combination of A+ and T+ (or N+) conveyed a greater risk than A‐T‐N‐ or isolated A+ or T+ (Figure 1). ROC analyses revealed that only tau‐PET performed better than demographics alone when predicting all‐cause dementia while both amyloid‐ and tau‐PET performed better than demographics and MRI when predicting AD dementia. LASSO logistic regression revealed that the optimal model to predict conversion from MCI to all‐cause dementia included a quantitative MRI marker and tau‐PET visual read. For optimal prediction of AD dementia specifically, the quantitative measure of amyloid‐PET was added in addition to the quantitative MRI marker and the tau‐PET visual read (Table 2).

Conclusion

Among individuals with MCI, tau‐PET performs best when predicting dementia, and can be optimized when combined with MRI. For AD dementia, tau‐PET and amyloid‐PET are the best‐performing modalities, but an optimal prediction is again achieved when combined with MRI.
Impact of sharing Alzheimer’s disease biomarker results with individuals without dementia: a systematic review and meta‐analysis of empirical data
Authors: van der Schaar Jetske , Visser Leonie N.C. , Ket Johannes C.F. , Groot Colin , Pijnenburg Yolande A.L. , Scheltens Philip , Bredenoord Annelien L. , Hoven Mariette A. , van der Flier Wiesje M.
Published: December 2023

Background

A biological definition of Alzheimer’s disease (AD) is increasingly used in research, but little is known about the consequences of early biomarker testing from the perspective of professional (healthcare professionals) and personal (citizens, patients, and their families) stakeholders. We aim to provide a systematic literature review and meta‐analysis of empirical evidence on expected and experienced implications of sharing AD biomarker results with individuals without dementia.

Method

We searched PubMed, Embase, APA PsycINFO, and Web of Science Core Collection on 10 November 2021 for literature on sharing AD biomarker results with individuals without dementia. Two reviewers independently screened 8034 titles and abstracts, and 192 full‐text records, for eligibility. Results from included studies were synthesized and quantitative data on psychosocial impact (anxiety, depression, stress, and suicidal ideation) were meta‐analyzed using a random‐effects model.

Result

We included 33 publications (20 quantitative and 13 qualitative data). Of these, eight reported on professional stakeholders’ attitudes and practices, 13 on personal stakeholders’ expectations, and 12 on their actual experiences. Most professional stakeholders valued biomarker testing, believing the benefits outweigh the risks, although attitudes and practices varied considerably. Most personal stakeholders expressed interest in (hypothetical) biomarker assessment, expecting to gain insight, reduce dementia risk and prepare for the future. Studies evaluating actual experiences found that sharing negative biomarker results led to relief and sometimes frustration for not having an explanation for concerns, while positive biomarkers prompted anxiety but also clarity. Those tested positive intended to adapt their lifestyle and plans, yet some worried about stigmatization. The majority did not regret being informed. Meta‐analysis of 5 studies including 2012 participants (elevated amyloid = 1324, asymptomatic = 1855) showed that short‐term psychological impact was not significant when considering all participants (random‐effect estimate = 0.026, SE = 0.018, p = 0.153), nor biomarker‐positive (estimate = 0.012, SE = 0.019, p = 0.538), or biomarker‐negative individuals (estimate = 0.061, SE = 0.043, p = 0.154) separately.

Conclusion

Most personal stakeholders indicate they wish to know their AD biomarker status. While sharing results could induce mixed emotions, it does not cause short‐term psychological harm and may offer actionability. There is a need for developing and harmonizing guidelines for biomarker testing and sharing results, particularly in view of the imminent advancements in disease‐modifying treatment.
Time‐encoded ASL shows higher sensitivity to detect cerebral blood flow reductions in AD
Authors: Falcon Carles , Montesinos Paula , Vaclavu Lena , Minguillon Carolina , Fauria Karine , Suarez‐Calvet Marc , Grau‐Rivera Oriol , Puig‐Pijoan Albert , Cascales‐Lahoz Diego , Contador José , Fernández‐Lebrero Aida , Navalpotro Irene , Van Osch Matthias J.P. , Sanchez‐Gonzalez Javier , Gispert Juan Domingo
Published: December 2023

Background

Pseudo continuous arterial spin labelling (pcASL) is an MRI technique to quantify cerebral blood flow (CBF). Time encoded ASL (te‐ASL) is a multiple time‐point pcASL variant that by acquiring several post‐label delays (PLD) to have more accurate CBF estimation allowing to measure arterial‐transit time (ATT). The aim of this study was to assess the performance of te‐ASL in detecting CBF and ATT changes in the Alzheimer’s disease (AD) continuum.

Method

The sample consisted of 59 subjects: 25 healthy controls (HC), 17 cognitively unimpaired individuals with positive cerebrospinal fluid (CSF) biomarkers (Ab42<1.098pg/mL; p‐Tau181>19pg/mL; Elecsys® ‐Roche Diagnostics) (preAD) and 17 patients with clinical diagnosis of AD (Ab42/p‐Tau181 ratio <10.25; Lumipulse‐Fujirebio). The MRI protocol comprised of anatomical T1, and ASL sequences (M0 and te‐ASL). CBF and ATT maps were calculated in the oxford_asl toolbox in FSL. CBF and ATT maps were spatially normalized to the MNI, smoothed (12mm FWHM) and intensity normalized to the cerebellar gray matter. To detect patterns of lower CBF, voxel‐wise one way 3‐group ANOVA and post‐hoc paired t‐tests were performed using age and sex as confounders (SPM12; statistical threshold: p<0.001 uncorrected; k>100 voxels (∼0.33cm3) in all analyses). We compared results with those obtained using a single PLD by computing CBF from the last PLD (perfusion block, nominal PLD time of 2000ms) of the te‐ASL schema.

Result

Table 1 displays the descriptive statistics of the sample. Figure 1 shows that, with te‐ASL, AD patients displayed lower CBF (yellow) in extensive bilateral pareto‐temporal, cingulate and occipital areas. Preclinical AD participants showed an overlapping pattern (green), albeit reduced in extension. When using pcASL, the detected pattern of lower CBF in the AD group was less extended and did not overlap with that of the PreAD groups. No ATT differences were found associated to AD.

Conclusion

te‐ASL was more sensitive to detect CBF differences across the AD continuum than single PLD ASL. The pattern of lower CBF in the AD group covered expected areas, and that in the preclinical AD group partially overlapped.
Associations between homocysteine, tau, and neurodegenerative markers in apolipoprotein ε4 non‐carriers with clinical Alzheimer’s disease
Authors: Lin William Z. , Yu Di , Xiong Lisa Y. , Goubran Maged , Ozzoude Miracle , Kumar Sanjeev , Tang‐Wai David F. , Tartaglia Carmela , Tan Brian , Bartha Robert , Haddad Seyyed M. H. , Nanayakkara Nuwan D. , Symons Sean , Lou Wendy , MacIntosh Bradley J. , Lanctôt Krista L. , Zetterberg Henrik , Black Sandra E. , Swardfager Walter
Published: December 2023

Background

Homocysteine (Hcy) is an amino acid generated as a byproduct of methionine metabolism. It is a risk factor for vascular and neurodegenerative diseases. This study investigated relationships between plasma Hcy concentrations and neurodegenerative biomarkers in people clinically diagnosed with Alzheimer’s disease (AD) or mild cognitive impairment (MCI) due to AD.

Method

Participants were identified from the Ontario Neurodegenerative Disease Research Initiative. Brain parenchymal fraction (BPF) was quantified using T1‐ and T2‐weighted structural magnetic resonance imaging with an in‐house Semi‐Automated Brain Region Extraction and Lesion Explorer package. Plasma amyloid beta (Aβ) 42, Aβ40, phosphorylated tau 181 (p‐tau181), and neurofilament light chain (NfL) were measured with Single molecule array (Simoa) assays. Linear regression analyses were used to test associations between Hcy and neuroimaging or plasma biomarkers, controlling for age, sex, hypertension, hyperlipidemia, diabetes, cholesterol, and vitamin B12. Analyses were stratified by apolipoprotein E (APOE) ε4 carrier status (non‐carriers: n = 64, mean age = 70.9 years, 41% female; carriers: n = 62, mean age = 71.2 years, 50% female).

Result

In APOE ε4 non‐carriers, Hcy was associated negatively with BPF (β = ‐0.233, p = 0.047, 95% CI [‐0.460, ‐0.003]), notably in temporal lobe regions in exploratory regional analyses. Hcy was also associated positively with plasma concentrations of NfL (β = 0.403, p = 0.007, 95% CI [0.117, 0.688]) and p‐tau181 (β = 0.357, p = 0.023, 95% CI [0.051, 0.663]) in APOE ε4 non‐carriers. Also, in APOE ε4 non‐carriers, Hcy was associated positively with Aβ40 (β = 0.367, p = 0.015, 95% CI [0.074, 0.660]) and Aβ42 (β = 0.305, p = 0.041, 95% CI [0.012, 0.598]), but not with the Aβ42/40 ratio (β = 0.155, p = 0.339, 95% CI [‐0.166, 0.476]). None of these associations were seen in APOE ε4 carriers.

Conclusion

In non‐carriers of the APOE ε4 allele clinically diagnosed with AD or MCI, homocysteine was associated with Amyloid, tau and neurodegeneration. The specificity of these relationships to ε4 non‐carriers identifies a unique risk factor profile for AD that is independent of APOE ε4 status.
Are elderly patients with atrial fibrillation sufficiently anticoagulated?
Authors: Trydal Espen Knut , Ajmi Soffien Chadli , Nygaard Benedikte Lea , Kallevag Oystein , Kurz Kathinka Dehli , Kurz Martin Wilhelm
Published: December 2023

Background

Epidemiological and clinicopathological data show a significant overlap between cerebrovascular disease (CVD) and Alzheimer’s disease (AD)[1]. Atrial fibrillation (AF) is a significant risk factor for both stroke[2], and cognitive decline, and is also associated with all kinds of dementia including AD[3,4] (though a shared patho‐mecanism might be a factor in the link with AD[5]). As the elderly have a higher prevalence of cerebrovascular disease and AF, we wanted to explore the effect of age on anticoagulation status.

Method

From 2009 to 2022, we prospectively registered all acute stroke patients treated with endovascular thrombectomy (EVT). We recorded stroke‐risk factors, including atrial fibrillation and the status of anticoagulation. To examine a possible age inequality, we analyzed the effect of age over and under 80 years on anticoagulation status.

Result

438 patients were treated with EVT. The median age was 74 (IQR 63‐81). The median NIHSS before EVT was 17 (IQR 11‐21). 71 patients (16%) had a history of myocardial infarction and 59 patients of previous cerebral stroke (14%). 246 patients (56%) had hypertension, 61 (14%) diabetes, and 171 (39%) were diagnosed with AF. In 80 patients (18%), AF was newly diagnosed, and 97 (22%) had known AF. 60 patients (13.7%) were inadequately anticoagulated at admission. When dichotomizing around the age of 80, significant more elderly patients with AF were insufficiently anticoagulated compared to younger patients (43% vs 26%, p<0.018). Age as a variable was significantly associated with insufficient anticoagulation (p<0.001).

Conclusion

In this prospectively followed group of patients treated with EVT, a significant number of elderly patients with AF were insufficiently treated with anticoagulantia. Age was identified as a highly significant risk factor for inadequate anticoagulation. We suggest further studies addressing the association of AF with cognitive decline, dementia and AD, and especially the role of insufficient anticoagulation. We advocate improvements in the prophylactic treatment of AF in the elderly.

1. Whitmer, et al. Neurology. 2005Jan;277‐81.

2. Wolf, et al. Stroke. 1991Aug;983‐8.

3. Diener, et al. Journal of the American college of cardiology. 2019Feb;612‐9.

4. Bunch, et al. Heart rhythm. 2010Apr;433‐7.

5. Myers, et al. Frontiers in aging neuroscience 2022Jul
The effect of Alzheimer’s disease pathology in corticobasal syndrome and progressive supranuclear palsy
Authors: Cordero Indira Ruth Garcia , Anastassiadis Chloe , Khoja Abeer , Morales‐Rivero Alonso , Vasilevskaya Anna , Thapa Simrika , Davenport Carly , Sumra Vishaal , Tang‐Wai David F. , Couto Blas , Multani Namita , Taghdiri Foad , Anor Cassandra Jessica , Varriano Brenda Maricela , Misquitta Karen , Fox Susan , Kovacs Gabor G. , Boxer Adam L. , VandeVrede Lawren , Lang Anthony E , Tartaglia Carmela
Published: December 2023

Background

Corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) display phenotypic heterogeneity. CBS pathology can include 4‐repeat (4‐R) tau and Alzheimer’s disease (AD) pathology/co‐pathology; while PSP involves predominantly 4‐R tau with AD co‐pathology. We evaluated whether in vivo biomarkers of AD pathology in CBS and PSP are associated with specific brain atrophy and default mode network (DMN) alterations and relates to specific clinical manifestations.

Method

We analyzed MRIs of 110 patients with a clinical diagnosis of CBS and PSP from 4RTNI‐1, 4RTNI‐2 and the Toronto Western Hospital and 30 healthy controls. Patients were separated according to AD biomarker positivity (CBS/PSP‐AD, n = 23) and negativity (CBS/PSP‐noAD, n = 87) based on blood and cerebrospinal fluid AD biomarkers. Patients’ cortical and subcortical volumes were obtained using Freesufer segmentation and compared against controls. The DMN connectivity was compared across groups using two‐sample t‐tests. In a subgroup of patients, we analyzed Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), PSP Rating Scale (PSPRS) and delayed memory on the California Verbal Learning Test (CVLT). Spearman partial correlations were performed to relate the PSPRS and CVLT scores with whole‐brain grey matter volumes. Neuroimaging analyses were controlled for age, site and total intracranial volume.

Result

CBS/PSP‐AD displayed atrophy in temporal and parietal regions and hippocampus; while CBS/PSP‐noAD, in frontal and temporal regions, basal ganglia and thalamus (p<0.05, Bonferroni corrected). Reduced connectivity within the DMN was found in frontal‐temporal regions for CBS/PSP‐AD, and in frontal‐parietal regions for CBS/PSP‐noAD versus controls; and in temporal regions for CBS/PSP‐AD versus CBS/PSP‐noAD (p<0.001, uncorrected). No differences were obtained for MoCA, CDR and CVLT. The CBS/PSP‐AD group showed lower scores in the PSPRS in comparison to the CBS/PSP‐noAD [t(81) = 2.39, p = 0.02)]. Left thalamus grey matter volume negatively correlated with PSPRS scores [r:‐0.44, p = 0.02, Bonferroni corrected] in CBS/PSP‐noAD but no associations were found in CBS/PSP‐AD.

Conclusion

Distinct patterns of atrophy and connectivity were observed in CBS/PSP‐AD compared to CBS/PSP‐noAD, suggesting selective vulnerability to AD pathology. As well, severity of disease was related to thalamic atrophy only in CBS/PSP‐noAD. Selective vulnerability to diverse proteinopathies, leading to different atrophy and connectivity patterns, may help explain phenotypic heterogeneity in CBS and PSP.
Diagnosis patterns among diverse populations with mild cognitive impairment and Alzheimer’s disease: A large nationwide electronic health record cohort study
Authors: Sánchez‐Soliño Olga , Yue Emma Xiaomeng , Boroje Isabella , Vinikoor‐Imler Lisa C
Published: December 2023

Background

With recent advances and emerging research on diagnostic biomarkers and evolving diagnostic criteria, practitioners managing patients with cognitive complaints operate within a complex, changing environment. Although some evidence is available on the importance of prompt diagnosis, little information exists on the diagnostic process used in real‐world settings among diverse populations. This study’s objective was to characterize diagnosis patterns among adults with mild cognitive impairment (MCI), Alzheimer’s disease (AD), and/or dementia in the United States, and stratify by gender, age and race/ethnicity.

Method

This retrospective observational cohort study utilized the Optum® Market Clarity database from January 1, 2017–September 30, 2021. Eligible individuals had ≥1 diagnosis of MCI, AD, and/or dementia in their electronic health records or ≥2 diagnosis codes separated by ≥30 days in claims data, had ≥12 months of continuous enrollment before the cohort entry date, and had ≥1 day of continuous healthcare plan enrollment after the index date. Demographic information and the occurrence of diagnostic tests were also obtained from electronic medical records and insurance claims. Descriptive statistics were calculated and stratified by demographic factors.

Result

A total of 179,419 newly diagnosed MCI cases, 81,267 AD cases, and 338,739 dementia cases were identified. The mean age at MCI, AD, or dementia diagnosis was similar overall for males and females. Among Caucasians, the mean age of MCI diagnosis was 70.5±14.8 for females and 69.8±14.5 for males. Among African Americans, the mean age at MCI diagnosis was 66.3±15.4 for females and 63.6±16.1 for males. PET scans and CSF biomarker screening occurred less often than MRI and CT (MCI: PET 0.6%, CSF 1.6%, MRI 16.6%, CT 17.5%; AD: PET 0.5%; CSF 0.9%; MRI 9.0%; CT 18.4%; dementia: PET 0.2%; CSF 1.6%; MRI 9.5%; CT 25.9%).

Conclusion

The mean age at MCI, AD, and dementia diagnosis varied by demographic groups. The diagnosis of MCI, AD, and dementia remains largely clinical, with low use of brain imaging or CSF biomarkers. This knowledge of the patient populations and diagnostic experiences in a real‐world setting allows for greater understanding and growth to improve diagnosis across diverse groups and lead to faster support.
Education and cognitive function among older adults in Brazil and Mexico
Authors: Gonçalves Natalia G , Avila Jaqueline Contrera , Bertola Laiss , Obregon Alejandra Michaels , Ferri Cleusa P , Wong Rebeca , Suemoto Claudia Kimie
Published: December 2023

Background

Education is a protective factor against cognitive impairment. Research on education and cognitive function has focused on high‐income countries, where education is higher. Thus, it is important to investigate this association in a context of lower education levels, such as the one in middle‐income countries. We use nationally representative data from the two largest countries in Latin America, Mexico and Brazil, to assess the benefits of education for cognitive function, and assess how sex and country modify this relationship.

Methods

The sample included adults 50 years or older from the 2015 waves of the Brazilian Longitudinal Study of Aging (ELSI) (n = 9,412) and the Mexican Health and Aging Study (MHAS) (n = 14,779). Participants were classified as cognitively impaired or not impaired using cognitive performance scores and a regression‐based approach. Education was categorized as 0, 1‐4, 5‐8, or >8 years of education. We used logistic regression models to estimate the association of education with cognitive function adjusted for sociodemographic variables, chronic diseases, and health behaviors. We also investigated the modifying effec of sex and country by adding an interaction term in the fully adjusted model.

Results

Participants of the ELSI had mean age 62.5±9.8 years, 54% were women, 13.3% had no formal education, and 6% were categorized as cognitively impaired. Participants of the MHAS had mean age 64.8±9.7 years, 55% were women, 18% had no formal education, and 5% were categorized as cognitively impaired (Table 1). Individuals with at least one year of education were less likely to have cognitive impairment than those with no formal education in both countries, with the highest reduction in the >8 years category, followed by the 1‐4 and the 5‐8 education categories (Table 2). We found a three‐way interaction effect of education with country and sex (p<0.001). Men in the MHAS had lower odds of cognitive impairment than men in the ELSI at all levels of education, but there was no difference for women (Figure 1).

Conclusion

Higher educational level was associated with lower odds of cognitive impairment in both countries. Men in Brazil had higher odds for cognitive impairment compared with men in Mexico.
Presynaptic and axonal loss are synergistically associated with longitudinal neurodegeneration and cognitive decline
Authors: Shi Dai , Lan Guoyu , Cai Yue , Li Anqi , Zhu Yalin , Zhou Liemin , Guo Tengfei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Both presynaptic losses measured by cerebrospinal fluid (CSF) growth‐associated protein 43 (GAP‐43) and axonal degeneration detected by plasma neurofilament light (NfL) may be related to neurodegeneration and cognitive decline. However, it is still not fully understood whether CSF GAP‐43 and plasma NfL have a synergistic effect on predicting longitudinal neurodegeneration and cognitive decline.

Method

We identified 730 Alzheimer’s Disease Neuroimaging Initiative participants (233 cognitively unimpaired (CU), 387 mild cognitive impairment (MCI), and 110 AD dementia) with concurrent (interval < 1 year) CSF GAP‐43, plasma NfL, and longitudinal memory and executive function data. Among them, 706 participants (225 CU, 388 MCI, 93 AD dementia) had longitudinal measurements of residual hippocampal volume (rHCV) and temporal metaROI cortical thickness, and 366 participants (108 CU, 235 MCI, 23 AD dementia) had longitudinal data of metaROI 18F‐fluorodeoxyglucose (FDG) standard uptake value ratio (SUVR). We investigated the interaction of baseline CSF GAP‐43 and plasma NfL at longitudinal prediction of rHCV, temporal metaROI cortical thickness, metaROI FDG SUVR, memory, and executive function, controlling for age, sex, education, and diagnosis.

Result

Higher CSF GAP‐43 and Plasma NfL at baseline had significant interaction (p = 0.028) on predicting faster rates of temporal metaROI cortical thinning but not on longitudinal decreases of rHCV and metaROI FDG SUVR (Figure 1). In addition, given the same levels of CSF GAP‐43, higher baseline plasma NfL was related to more rapid rates of decline in memory (p = 0.022) and executive function (p = 0.004) over more than 4 years of median follow‐up (Figure 2).

Conclusion

We found a synergistic effect between presynaptic dysfunction and axonal degeneration on predicting longitudinal cortical thinning and cognitive decline. These findings provide novel insights into understanding the association of presynaptic and axonal loss with subsequent neurodegeneration and cognitive decline in elderly adults.
Impact of sex, age, and ancestry on Apolipoprotein E‐APOE‐ risk for Alzheimer’s disease
Authors: Rodriguez Omar Garcia , Young Juan I. , Wang Lily ,   Alzheimer’s Disease Genetics Consortium (ADGC), Martin Eden R. , Kunkle Brian W.
Published: December 2023

Background

Previous studies have reported that non‐Hispanic White (NHW) females carrying the APOE ε4 allele have an increased risk for developing AD when compared to men. Recently, analyses showed that the risk for developing AD may be equivalent for males and females but may differ by age. Few studies have been done on this issue in groups other than NHW. We aimed to evaluate the association between sex, age, ancestry, APOE, and AD.

Methods

We conducted a pooled case‐control study from 45 independent databases in Alzheimer’s Disease Genetics Consortium. Individuals (age≥55 years) were included (n = 31,058). Independent variables were age, sex, ancestry/ethnicity, and APOE genotype (ε3/ε4 vs. ε3/ε3). Logistic, linear, and Cox regression models were performed by sex and ancestry.

Results

Regardless of ancestry, men and women with APOE ε3/ε4 showed no significant difference in the risk of developing AD (all age groups combined). When comparing subjects with APOE ε3/ε4 to those with ε3/ε3, East‐Asian (EA) females (OR,4.90; 95% CI: 3.46‐6.95) had the strongest OR, followed by EA males (OR, 4.09: 2.67‐6.27); and NHW females (OR,3.40: 3.14‐3.68) and men (OR,3.33: 3.03‐3.66) among all ethnicities. When stratified by age, NHW females (OR, 3.41: 2.69‐4.32 vs. NHW males: OR,2.57: 1.94‐3.39) and EA women (OR,6.51: 1.31‐32.30 vs. EA men: OR,3.41: 0.66‐17.56) with APOE ε3/ε4 showed a higher risk of developing AD between ages 55‐65; whereas African American (AA) women (OR,4.14: 3.06‐5.60 vs. AA men: OR,2.27: 1.45‐3.55) exhibited this pattern later, at the age of 66‐75 years. In Hispanics, the pattern is reversed, with males aged 55‐65 years carrying APOE ε3/ε4 (OR,6.65; 1.64‐26.89: vs. females: OR,2.27; 1.03‐4.98) had a stronger association with AD risk than their female counterpart. Case‐only and survival analyses also showed that NHW and EA female carriers of APOE ε3/ε4 had an earlier age at the onset of AD than their counterpart in men.

Conclusions

Our findings suggest sex differences by age and ethnicity in the risk for developing AD and age at onset of AD for carriers of APOE ε4. Confirming these findings could lead to a better‐personalized risk assessment for AD that accounts for sex differences in APOE.
Longitudinal multi‐day learning curves (MDLCs) to capture subtle cognitive changes in preclinical Alzheimer’s disease
Authors: Jutten Roos J. , Soberanes Daniel , Weizenbaum Emma L , Hsieh Stephanie , Molinare Cassidy , Johnson Keith A. , Rentz Dorene M. , Sperling Reisa A. , Amariglio Rebecca E. , Papp Kathryn V.
Published: December 2023

Background

Remote digital testing provides the opportunity to deploy memory paradigms that mimic learning in everyday life by exposing participants to repeated stimuli over frequent intervals. Here, we used the Boston Remote Assessment for Neurocognitive Health (BRANCH) multi‐day learning curve (MDLC) paradigm and investigated whether repeating MDLCs over time could capture subtle cognitive changes in preclinical Alzheimer’s disease (AD).

Method

N = 223 cognitively unimpaired older adults (age = 74±8.1, 65% female, MMSE 29±1.4) with standardized cognitive testing and amyloid and tau PET from the Harvard Aging Brain Study completed a modified version of the Face‐Name Association Examination (FNAME) at‐home for seven consecutive days on a personal device. After 10.8±2.6 months a subsample (n = 54; age = 75±8.8, 61% female, MMSE = 29±1, 19% Aβ+, n = 51 with tau PET) completed a second version of the FNAME with new stimuli for seven consecutive days. A summary learning curve metric for each MDLC (baseline and follow‐up) was computed using an Area Under the Curve (AUC) method allowing for the combination of Day 1 performance and a learning trajectory over the subsequent six days. We used linear mixed effect (LME) models on the MDLC AUCs to investigate change in MDLCs and compared this to change in Day 1 performance of the MDLCs. We also ran LME models adjusting for demographic factors to examine whether baseline Preclinical Alzheimer’s Cognitive Composite‐5 (PACC5) performance and amyloid and tau burden were associated with change in MDLCs.

Result

Overall, MDLCs diminished over time (Time = ‐0.028, 95%CI[‐0.056 – ‐0.001], p = 0.047) which was not detected by change in Day 1 performance of the MDLC (Time = ‐0.026, 95%CI[‐0.063 – 0.012], p = 0.117). A lower MDLC at follow‐up compared to baseline was associated with elevated amyloid (Aβ+ Group*Time = ‐.08, [95%CI = ‐0.15‐ ‐0.01], p = 0.042) (Figure 1) and worse PACC5 performance (PACC5*Time = 0.05, 95%CI = [0.01‐0.09], p = 0.029) (Figure 2). Greater entorhinal tau burden was associated with a lower baseline MDLC (Tau = ‐0.18, 95%CI[‐0.34 – ‐0.03], p = 0.025) but not with MDLC change over time.

Conclusion

These results highlight how capturing multiple datapoints over days detects short‐term cognitive changes in preclinical AD that are undetectable using standard single timepoint assessments. Paradigms such as BRANCH MDLC may thereby offer more sensitive cognitive outcome measures for AD secondary prevention trials.
Retromer pathways can regulate AD‐associated neuronal and microglial phenotypes
Authors: Qureshi Yasir H
Published: December 2023

The relationship between retromer‐dependent pathways in neurons and neighboring glial remains unknown. To address this question, we turn to a genetic mouse model where the retromer core protein VPS35 is depleted in hippocampal neurons, and then we replete VPS35 using an optimized viral vector protocol. The VPS35 depletion‐repletion studies strengthen the causal link between the neuronal retromer and AD‐associated neuronal phenotypes, including the acceleration of amyloid precursor protein cleavage and the loss of synaptic glutamate receptors. More interestingly, the studies show that the neuronal retromer can regulate a distinct, dystrophic, microglia morphology, phenotypic of hippocampal microglia in AD. Finally, the neuronal and, in part, the glial responses to VPS35 depletion were found to occur independent of tau. Future studies are required to determine the mechanisms by which retromer‐dependent dysfunction in neurons provokes neighboring microglia.
Clinically relevant factors for blood‐based Alzheimer biomarker interpretation
Authors: Zetterberg Henrik
Published: December 2023

Background

Blood‐based biomarkers for Alzheimer disease (AD)‐related processes are moving towards large‐scale clinical implementation at a very rapid pace. Maintaining diagnostic performance when moving from group‐level data in well‐curated clinical cohorts to individual diagnostics in real‐world clinical settings can be challenging. This presentation gives an updated account of clinically relevant factors that may influence AD blood biomarker concentrations in individual patients.

Methods

Blood‐based AD biomarker data (amyloid β 42/40 ratio [Aβ42/Aβ40], phosphorylated tau forms [P‐tau], neurofilament light [NfL], and glial fibrillary acidic protein [GFAP]) from human experimental and observational cohort studies were summarized and examined in relation to demographic data, including age, sex, race, ethnicity, body mass index (BMI), as well as kidney and liver function tests, other co‐morbidities, drugs, and food intake.

Results

In most cohorts, age, creatinine, and BMI were associated with NfL, GFAP, and to a lesser extent p‐tau, but their diagnostic performances were not severely influenced. In general, there were no or only minor effects of common co‐morbidities and medications on AD blood biomarker concentrations. However, individual drugs may have strong effects. For example, a drug affecting microglial activity (minocycline), increased plasma NfL concentration several‐fold, and treatment with a neprilysin inhibitor against heart failure decreased plasma Aβ42/Aβ40 (determined by immunoassay) by ∼30%, i.e., with an effect size greater than what is caused amyloid plaque pathology. Surprisingly, intake of a standardized meal reduced plasma NfL, GFAP, and P‐tau (181 and 231) concentrations by 10‐20% after two hours, which is an effect similar in size to what has been seen in anti‐Aβ antibody trials. Across cohorts and biomarkers, plasma Aβ42/Aβ40 appeared to be the most resistant to these types of confounding factors.

Conclusion

Moving from group level interpretation in research to individual diagnostics in clinical practice requires special attention to unusual biomarker results and improved knowledge of clinically important confounders. Some of this knowledge will be gained in clinical practice by thoughtful biomarker interpretation and knowledge exchange between clinical and laboratory specialists. Some confounding factors may be assay‐specific. Continued intense collaboration between clinics and laboratories, as well as method comparison and refinement studies, will be highly important.
Tracing the spatial extent of cortical tau over time in Alzheimer’s disease
Authors: St‐Onge Frederic , Binette Alexa Pichet , Chapleau Marianne , Breitner John C.S. , Villeneuve Sylvia
Published: December 2023

Background

Neuropathological studies defined the paradigm that tau—the pathological hallmark of Alzheimer’s disease (AD)—spreads homogenously across individuals from the medial temporal lobe to the neocortex. This staging system is referred to as Braak stages. However, neuroimaging studies have since highlighted significant inter‐regional and inter‐individual differences in tau spreading patterns. We investigated the spatial extent of cortical tau over time in the amnestic AD spectrum.

Method

We included 195 amyloid‐positive ADNI participants that had at least two tau‐PET scans (90 cognitively unimpaired [CU], 66 with mild cognitive impairment [MCI], 39 with AD dementia; average follow‐up 2.6 years). We derived regional thresholds of tau positivity for 64 cortical regions and the amygdalae using Gaussian mixture modeling and applied them to all tau scans. The same approach was used to obtain thresholds for composite regions corresponding to the Braak stages. For each region, we calculated the rate of change in the amount (i.e., standardized uptake value ratio [SUVR] change) of tau pathology and the annual change in the positivity status (i.e., spatial extent change). These rates were compared between diagnostic groups using linear mixed models.

Result

Across diagnostic groups, change in tau positivity followed Braak staging; over 90% of participants positive at follow‐up either progressed or were already positive on a previous Braak stage at baseline (Fig‐1AI) and greater SUVR change was observed in temporal regions (Fig‐1B). However, across the brain, there was heterogeneity between individual patterns of tau positivity progression (Fig‐1AII). This heterogeneity was most striking in MCI patients, where many regions progressed from low to high levels of tau (Fig‐1C). Regional SUVR change did not differ between participants with AD or with MCI (Fig‐2A), but participants with MCI showed the fastest change in regional positivity compared to participants with AD and CU participants. (Fig‐2B)

Conclusion

While tau propagation follows Braak staging, inter‐individual differences can be found by considering a fine‐grained approach of regional progression to positivity. Furthermore, participants with MCI have the highest number of regions becoming abnormal annually. Our research pushes the importance of considering the entire brain when studying change in tau pathology, particularly before AD diagnosis.