bluuebunny/crossref_metadata_2025 huggingface dataset:
Detecting short‐interval longitudinal cortical atrophy in neurodegenerative dementias via cluster scanning: A proof of concept
Authors: Katsumi Yuta , Brickhouse Michael , Hanford Lindsay C. , Nielsen Jared A. , Elliott Maxwell L. , Mair Ross W. , Touroutoglou Alexandra , Eldaief Mark C. , Buckner Randy L. , Dickerson Bradford C.
Published: January 2025

Background

Regional brain atrophy estimated from structural MRI is the most widely used measure of neurodegeneration in Alzheimer’s disease (AD), Frontotemporal Lobar Degeneration (FTLD), and other dementias. Yet, traditional MRI‐derived morphometric estimates are susceptible to measurement errors, posing a challenge for reliably detecting longitudinal atrophy, particularly over short intervals. We examined the utility of multiple accelerated MRI scans acquired in rapid succession (i.e., “cluster scanning”) for detecting longitudinal cortical atrophy over 3‐ and 6‐month intervals within individual patients.

Method

Four individuals with mild cognitive impairment or mild dementia likely due to AD or FTLD participated (see Table 1 for demographic and clinical characteristics). At baseline, 3 months, and 6 months, structural MRI data were collected on a 3 Tesla scanner using a fast multi‐echo (ME) MPRAGE sequence (acquisition time = 2’23’’, TR = 2200ms, TEs = 1.57/3.39/5.21/7.03ms, field of view = 192×192mm2, 144 slices, 4x GRAPPA acceleration, 1.2mm isotropic voxels). At each timepoint, participants underwent 32 MEMPRAGE scans acquired in four sessions over two days. Each MRI acquisition was processed with FreeSurfer version 6.0.0 using the recon‐all pipeline to derive a sample of estimates of cortical thickness at each timepoint. An independent, standard MEMPRAGE scan acquired prior to this study was used to define vertex‐wise regions of interest (ROI) masks for each participant compared to a group of cognitively unimpaired participants, representing phenotypically vulnerable regions expected to show longitudinal atrophy (“core” atrophy ROIs) and regions with no atrophy (“control” ROIs).

Result

Figures 1 summarizes the results obtained from a linear mixed effects model constructed separately for each participant. We found a Timepoint x ROI interaction in three of the four participants (all p≤0.0049), driven primarily by core regions exhibiting longitudinal atrophy of a greater magnitude from baseline to 3 months (n = 3) and to 6 months (n = 2) compared with control regions. In all four participants, core regions showed longitudinal atrophy from baseline to 3 months and to 6 months (all p<0.0001).

Conclusion

These findings provide proof‐of‐concept evidence that pooling multiple morphometric estimates derived from fast MRI acquired in clusters enables the detection of cortical atrophy over short intervals in individual patients with neurodegenerative dementias.
Molecular correlates of neural health associate with cardiovascular states
Authors: VandeBunte Anna M. , Ortiz Bailey L , Paolillo Emily W. , Dutt Shubir , Sible Isabel , Chan Brandon , Lago Argentina Lario , Rojas Julio C. , Saloner Rowan , Cadwallader Claire J. , Chen Coty , Diaz Valentina E. , Callies Lana S. , Hallgarth Savannah R. , Tucker Miwa , Kramer Joel H. , Casaletto Kaitlin B.
Published: January 2025

Background

Suboptimal cardiovascular health poses a significant risk for dementia, yet biological links between cardiovascular health and brain function are poorly understood. We examined how plasma markers of astrocytic activation (GFAP), neuronal axon breakdown (NfL), and Alzheimer’s disease (AD) pathology (pTau181) relate to several behavioral and risk indicators of systemic cardiovascular health in older adults along the AD continuum.

Method

209 older adults (59% female; 88% clinically normal; 15% amyloid PET+) completed 30‐day FitbitTM Flex2 monitoring (average daily steps), blood pressure (BP) and heart rate quantification, and plasma assayed for GFAP, NfL, and pTau181 (Quanterix Simoa). Regression models evaluated associations among indicators of cardiovascular health (pulse pressure [systolic BP‐diastolic BP], systolic BP, physical activity, resting heart rate) and plasma markers. Post‐hoc mediation models (1000 bootstrap resampling) evaluated mediational relationships among vascular health indicators and NfL. Models adjusted for age, sex, and BMI.

Result

Elevated pulse pressure associated with higher plasma pTau181 (β = 0.21, p<0.01), NfL (β = 0.19, p<0.01), and GFAP concentrations (β = 0.16, p = 0.01). Higher systolic BP associated with higher plasma pTau181 (β = 0.18, p = 0.03) and NfL concentrations (β = 0.19, p<0.01). Greater average daily steps associated with lower plasma NfL (β = ‐0.15, p = 0.04, but not pTau181 (β = ‐0.10, p = 0.27) or GFAP (β = ‐0.13, p = 0.057). Resting heart rate did not associate with plasma biomarker concentrations (ps>0.50). Given physical activity is a cardiovascular behavior that may support vessel health, we tested a post‐hoc mediation model examining if systolic BP or pulse pressure mediated the association between step count and NfL. Systolic BP, but not pulse pressure, fully mediated the relationship between daily steps and plasma NfL (Indirect Pathway: β = ‐0.04, p = 0.03; Direct Pathway: β = ‐0.11, p = 0.14).

Conclusion

Elevated pulse pressure and systolic BP associate with higher levels of AD pathology, astrocytic activation, and axonal degeneration (pTau181, GFAP, NfL), while greater average daily steps associated with lower levels of neurodegeneration (NfL). Systolic BP may drive the association between physical activity and axonal degeneration, highlighting the importance of BP management in mitigating the effects of neurodegeneration. Studying links among cardiovascular health indicators and molecular brain outcomes could inform precise intervention targets for optimal brain aging, such as promoting the importance of blood pressure control and physical activity engagement.
Validation of the plasma phosphorylated tau quantified using NUcleic acid Linked Immuno‐Sandwich Assay (NULISA) for the detection of Alzheimer’s disease pathology
Authors: Wang Yi‐Ting , Ashton Nicholas J. , Therriault Joseph , Benedet Andrea L. , Macedo Arthur C. , Pola Ilaria , Aumont Etienne , Molfetta Guglielmo Di , Arias Jaime Fernandez , TAN Kübra , Rahmouni Nesrine , Servaes Stijn , Isaacson Richard S. , Chan Tevy , Hosseini Seyyed Ali , Tissot Cécile , Mathotaarachchi Sulantha , Stevenson Jenna , Lussier Firoza Z , Pascoal Tharick Ali , Gauthier Serge , Blennow Kaj , Zetterberg Henrik , Rosa‐Neto Pedro
Published: January 2025

Background

Blood‐based biomarkers have been revolutionizing the detection, diagnosis and screening of Alzheimer’s disease (AD). Antibody‐based immunoassays are powerful tools to investigate pathological changes indicated by blood‐based biomarkers and have been studied extensively in AD research. A novel proteomic technology ‐ NUcleic acid Linked Immuno‐Sandwich Assay (NULISA) – was developed to improve the sensitivity of traditional proximity ligation assays and offer a comprehensive outlook for protein biomarkers in neurodegenerative diseases. Due to the relative novelty of the NULISA technology in quantifying AD plasma biomarkers, validation through comparisons with more established methods is required.

Method

In this present study, we assessed 397 participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort where participants had plasma measurements of p‐tau181, p‐tau217 and p‐tau231 from both NULISA and other established immunoassays. Participants also underwent neuroimaging assessments including MRI, amyloid and tau positron emission tomography (PET).

Result

Our findings suggest an excellent agreement between plasma p‐tau variants quantified using different immunoassays and strong associations with PET signals in the brain (Fig. 1). As shown in Figure 2, similar to p‐tau217 quantified using Janssen and ALZpath immunoassays, plasma p‐tau217
NULISA shows excellent discriminative accuracy for abnormal amyloid‐PET (AUC = 0.918, 95%CI: 0.883 to 0.953, P < 0.0001) and abnormal tau‐PET status (AUC = 0.939; 95%CI: 0.909 to 0.969, P < 0.0001). It also presents the capability for differentiating tau‐PET staging (Table 1).

Conclusion

Validation of the NULISA CNS panel adds to the current analytical methods for AD diagnosis, screening, and staging, and could potentially expedite the development of a blood‐based biomarker panel.
Human iPSC‐derived neuron modeling for the study of early‐onset Alzheimer’s disease
Authors: Valdes Phoebe , Caldwell Andrew B. , Liu Qing , Henry Kenneth W. , Fitzgerald Michael Q , Muralidharan Koushik , Ramachandran Srinivasan , Karch Celeste M. ,   Dominantly Inherited Alzheimer Network (DIAN), Yuan Shauna H , Wagner Steven L , Goldstein Lawrence S.B. , Mobley William C. , Galasko Douglas R. , Subramaniam Shankar
Published: January 2025

Background

Early‐onset Alzheimer’s disease (EOAD) is a complex disease that occurs at an early age at onset (AAO) before 65 years, constituting 5‐6% of all AD cases and remains poorly understood. Patient‐derived induced pluripotent stem cells (iPSCs) have been used to model different forms of EOAD that display heterogeneous disease mechanisms.

Method

We examined iPSC‐derived neurons from both familial EOAD harboring mutations in PSEN1A79V
, PSEN2N141I, and APPV717I
and non‐familial EOAD patients at an early AAO. RNA‐seq for familial and non‐familial EOAD patients as well as ATAC‐seq for familial EOAD patients were carried out to characterize the gene expression and chromatin accessibility changes, respectively. Differential expression and enrichment analysis, TF activity identification, and co‐expression module detection were performed for familial EOAD RNA‐seq. Clustering and surrogate neuron marker classification were performed for non‐familial EOAD RNA‐seq. Differential peak analysis, TF motif footprinting and peak functional enrichment were performed for familial EOAD ATAC‐seq.

Result

Our approach allowed us to identify the correlation between gene expression and chromatin accessibility associated with key disease familial EOAD endotypes. We identified limitations with our non‐familial EOAD neuron model to study sporadic AD, providing evidence that these neurons present variation of differentiation across patient clones, patient variability and an immature culture state. Common endotypes were identified across three familial EOAD mutations such as dedifferentiation of a mature neuron to a less differentiated quasi‐neuron state and repression of mitochondrial function and metabolism. Integrative analysis allowed us to ascertain the master transcriptional regulators associated with these endotypes, including REST, ASCL1, and ZIC family members (activation), as well as NRF1 (repression). Our non‐familial EOAD study showed a modest difference in expression profiling and a limited number of differentially expressed genes (DEGs) between diseased and control subjects.

Conclusion

iPSC‐derived neurons demonstrated that familial EOAD mutations share common regulatory changes within endotypes with varying severity, leading to reversion to a less‐differentiated neuron state. Extending the usage of these neurons to non‐familial EOAD may not serve as ideal to study sporadic AD. Overall, we have demonstrated that human neuron modeling can be applied to different forms of EOAD to understand the disease etiology better.
Regional amyloid shows associations with task‐related fMRI activation recorded 5 years earlier
Authors: Habeck Christian G , Stern Yaakov
Published: January 2025

Background

We were interested to test whether regional amyloid as measured with Florbetaben could be detected in fMRI activation patterns recorded 5 years prior.

Method

Perceptual Speed was probed with 3 cognitive fMRI tasks (Digit Symbol Substitution, Letter Comparison, Pattern Comparison) for 324 participants, aged 20 to 80, at timepoint 1. A subsample of 63 participants (aged 51‐80) underwent Florbetaben amyloid scans 5 years later ( = timepoint 2), resulting in SUVR values in 68 regions of the FreeSurfer DK atlas. For these 63 participants, Principal Components analysis was conducted in the activation data that were averaged within participant across all 3 tasks. Correlations of the resulting pattern scores with regional amyloid were observed, adjusting for the covariates of age, sex and years of education. The relationship to task performance in the fMRI tasks ( = sign‐reversed RT) was observed too, again with the covariates age, sex, and years of education. All participants were healthy, without cognitive impairment.

Result

The pattern score of the first principal component in the fMRI activation data in the subsample with N = 63 correlated with subsequent regional amyloid in 22 regions at p<0.05. In the larger sample of N = 324, the pattern score also correlated negatively with task performance, beyond the covariates of age, sex and years of education. The pattern consisted of positive loadings (Z>1.5) in frontal locations like anterior cingulate, superior and inferior frontal gyrus, bilateral insula, basal ganglia. The pattern showed negative loadings (Z←1.5) in occipital and cerebellar regions (see Figure).

Conclusion

Regional amyloid had a robust correlation with an underlying fMRI activation pattern for Perceptual‐Speed tasks collected 5 years earlier. While in the subsample of 63 there was no relationship of the pattern with fMRI‐task performance, in a whole lifespan sample with N = 324, the amyloid‐associated activation pattern was negatively related to task performance. These findings suggest that amyloid can impact activation in a manner that is detrimental to task performance even in healthy older adults.
Crystal structure of E2814 bound to Tau
Authors: Chen Yu , Vance James , Jacob Sara , Albone Earl , Ozaki Shunsuke , Phillips Corey , Shan Mingde , Kazarian Tom , Poun Bona , Choi Hyeong‐wook , Spidel Jared , Staddon James , Roberts Malcolm , Wang John
Published: January 2025

Background

E2814 is a humanized monoclonal antibody that recognizes the microtubule‐binding region (MTBR) of tau, a region of the protein essential for filament formation and propagation in neurodegenerative diseases. Epitope mapping showed that E2814 binds to a specific sequence motif HVPGG in the MTBR. To elucidate the atomic interactions of E2814‐tau binding, we performed X‐ray crystallography studies with E2814 and various tau peptides containing the HVPGG motif.

Method

The Fab fragment of E2814 was incubated with 5 different tau peptides containing the 299‐HVPGG‐303 epitope at a 1:10 molar ratio prior to co‐crystallization screening. Co‐crystals of E2814/tau peptides were grown by sitting drop vapor diffusion, and the diffraction data were collected at synchrotron. Structures of E2814 bound to tau peptides were determined by molecular replacement.

Result

Crystal structures of E2814 Fab bound to five tau peptides containing 299‐HVPGG‐303 epitope were determined at 1.44 –1.64 Å resolution. The comparison of the five crystal structures revealed the sequence 299‐HVPG‐302 of tau presents the core region mediating recognition by E2814, which is also facilitated by I297 in the flanking region. The tau peptides are accommodated in the recognition groove formed by CDR regions from the VH and VL domains, and exhibited a U‐shaped conformation with close‐to quarter turns when bound to E2814. Both H299 and P301 at the turns mediate major interactions with E2814.

Conclusion

Our results reveal the structural details of the key interactions between E2814 and the tau HVPGG motif, which adopts a U‐shaped conformation upon binding to E2814. These findings provide atomic insights into the mechanism of E2814‐mediated inhibition of tau aggregation and propagation.
Memory complaints after COVID‐19: a potential indicator of primary cognitive impairment or a correlate of psychiatric symptoms?
Authors: Dong Yiling , Ritto Ana Paula , Damiano Rodolfo Furlan , Coli Amanda Goulart , Hadade Rodrigo , Rocca Cristiana Castanho de Almeida , Serafim Antonio de Pádua , Guedes Bruno Fukelmann , Nitrini Ricardo , Forlenza Orestes Vicente , Filho Geraldo Busatto ,   HCFMUSP COVID‐19 Study Group
Published: January 2025

Cognitive impairment and symptoms of psychiatric disorders have been reported frequently as features of post‐acute sequelae of SARS‐CoV‐2 infection. This study aims to investigate subjective memory complaints in COVID‐19 survivors and determine if these are more strongly associated with objective cognitive impairment related to sequelae of SARS‐CoV‐2 infection or with symptoms of psychiatric conditions. A total of 608 COVID‐19 survivors were evaluated in‐person 6 to 11 months after hospitalization, with 377 patients assigned to a “no SMC” group and 231 patients assigned to an SMC group based on their Memory Complaint Scale scores. Follow‐up evaluations included an objective cognitive battery and scale‐based assessments of anxiety, depression, and post‐traumatic stress symptoms. We found the perception of memory impairment in COVID‐19 survivors to be more strongly associated to core symptoms of psychiatric conditions rather than to primary objective cognitive impairment. Univariate analysis indicated significant differences between the “no SMC” and SMC groups, both for the psychiatric symptom evaluations and for the cognitive evaluations (p<0.05); however, the psychiatric symptoms all had large eta‐squared values (ranging from 0.181 to 0.213), whereas the cognitive variables had small/medium eta‐squared values (ranging from 0.002 to 0.024). Additionally, multiple regression analysis indicated that only female sex and depressive and post‐traumatic stress symptoms were found to be predictors of subjective memory complaints. These findings may help guide clinical evaluations for COVID‐19 survivors presenting with memory complaints while also serving to expand our growing understanding of the relationship between COVID‐19, subjective memory complaints, and the risk of cognitive decline.
Racial and Ethnic Differences in Older Adults’ Financial Capacity and Differential Effects of Clinical Factors
Authors: Therrien Sarah , Li Oceanna Yueran , Lin Feng Vankee
Published: January 2025

Background

Financial capacity (FC) encompasses one’s ability to understand and complete financial tasks and is essential to older adults’ functional independence. FC is impacted by neuropsychological, neuropsychiatric, and everyday functioning factors in aging. In FC literature, much research does not include demographically representative samples. With a rapidly expanding proportion of older adults from racial and ethnic groups underrepresented in research, it is important to understand factors influencing independence in aging across all segments of the population. Some research shows several FC‐related clinical factors differ between non‐Hispanic white (NHW) and Black/African‐American (BAA) and Hispanic/Latino (HL) groups. Potential differential effects of these factors on groups’ FC are little understood. Here, we aim to understand racial and ethnic differences in FC and how clinical factors affect these relationships.

Method

We used data from ADNI participants with normal cognition, MCI, or AD dementia who completed Financial Capacity Instrument and identified as NHW, BAA, or HL (total n = 900). The Neuropsychiatric Inventory (NPI), Everyday Cognition (ECog) Scale, and Memory and Executive Function (EF) composite scores were used to evaluate clinical factors. Analysis on group differences, main effect of FC, and moderation and mediation analyses were conducted with the clinical stage controlled.

Result

BAA (Wald’s 2 = 15.06, p < .001), but not HL, had worse FC than NHW. In the entire sample there were significant correlations between FC and clinical factors (all 2 >7.60 and p<0.006). NPI was a significant moderator with FC in BAA was less impacted by NPI than in NHW (B = ‐0.49, SE = 0.19, Wald’s 2 = 6.84, p = .009). EF (B = ‐0.27, SE = 0.06, 95%CI:‐0.39, ‐0.15) and partner‐report ECog (B = ‐0.05, SE = 0.02, 95%CI: ‐0.09,‐0.01) were significant mediators for FC between BAA and NHW.

Conclusion

There are key differences in FC between racial and ethnic groups, especially between BAA and NHW older adults, with neuropsychiatric and neuropsychological factors affecting FC differently between groups.
Associations between Amyloid, Cardiovascular Risk, and Cognitive Function in Korean Older Adults: Insights from the KBASE Cohort
Authors: Chaudhuri Soumilee , Dempsey Desarae A. , Huang Yen‐Ning , Cao Sha , Chumin Evgeny J. , Craft Hannah , Crane Paul K. , Mukherjee Shubhabrata , Choi Seo‐Eun , Lee Michael L. , Scollard Phoebe , Mez Jesse , Trittschuh Emily H. , Klinedinst Brandon S , Nakano Connie , Hohman Timothy J. , Yi Dahyun , Byun Min Soo , Risacher Shannon L. , Nho Kwangsik , Saykin Andrew J. , Lee Dong Young ,   Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE)
Published: January 2025

Background

Understanding the relationship between cardiovascular burden, amyloid, and cognition in Alzheimer’s disease (AD) is essential for targeted interventions, especially in ethnically diverse populations where research remains limited. This study aimed to investigate these relationships in a cohort of Korean older adults along the AD spectrum.

Method

526 participants from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort were included in this study. Vascular burden was quantified using Framingham Risk Score (FRS) and participants were categorized into four groups based on combinations of FRS (FRS High or FRS Low with a median split) and amyloid status (Aβ+ or Aβ‐ based on a cut‐off of 1.2373). Cognitive function was evaluated using standardized neuropsychological tests processed with structural equation models to produce domain scores for memory, executive functioning, language, and visuospatial. ANOVA was employed at baseline to analyze cognitive differences among these groups and within each clinical diagnosis. Longitudinal mixed effects models spanning a period of four years from the initial visit captured cognitive changes over time within these groups (Figure 1).

Result

Significant group and pairwise differences were observed among the four groups in all cognitive domains (p < 0.0001). Stratified analysis within each clinical diagnoses group revealed that CN individuals in FRS high Aβ‐ demonstrated significantly lower memory scores compared to those with FRS low Aβ‐ (p < 0.0001), this trend was absent from MCI and AD groups (Figure 2). Longitudinally, FRS high Aβ+ and FRS low Aβ+ groups consistently demonstrated lower memory scores compared to the FRS low Aβ‐ group. Interestingly, no significant difference in cognition was observed between FRS high Aβ‐ and FRS low Aβ‐ groups over time. However, the most pronounced divergence in longitudinal cognition of the four FRS and Amyloid groups was observed within the MCI diagnosis group (Figure 3).

Conclusion

This study highlights the differential impact of cardiovascular risk on cognition depending on amyloid status and clinical diagnosis group. This underscores the importance of considering both cardiovascular risk factors and amyloid pathology early‐on in understanding clinical manifestation and cognitive decline in the AD spectrum, particularly in ethnically diverse populations.
Young Onset Neurocognitive Impairment, Amyloid Positivity, and Psychiatric Symptoms in Underrepresented Populations in the HABS‐HD Cohort
Authors: Culhane Julia E. , Arentoft Alyssa , Guzman Vanessa A. , Cham Heining , Byrd Desiree , Calcetas Amanda T. , Mindt Monica Rivera
Published: January 2025

Background

Adults from underrepresented populations (URPs), including non‐Latinx NLB (NLB) and Latinx adults, have higher Alzheimer’s disease and related dementia (ADRD) rates than non‐Latinx Whites (NLWs). Young onset dementia is diagnosed when symptom onset occurs before age 65, and little is known about mild cognitive impairment (MCI) and dementia rates in younger URPs. We examined neurocognitive diagnoses, amyloid positivity, and psychiatric symptoms in adults from URPs under 65.

Methods

A total of 1,562 participants under 65 (Mage = 57.8, SD = 4.18; Meducation = 13.08, SD = 4.09; Ethnocultural Status: 28.9% NLB, 46.2% Latinx, 24.9% NLW; Gender: 65.5% Female) from the Health and Aging Brain Study‐Health Disparities (HABS‐HD) completed a neuropsychological (NP) battery and received Clinical Dementia Rating Scale (CDR) scores. Study partners completed the Physician’s Estimate of Duration for AD‐related psychiatric symptoms (e.g., mood changes, anxiety/nervousness). Diagnoses (i.e., cognitively unimpaired (CU), MCI, dementia) were conferred using HABS‐HD consensus diagnosis criteria. A subset of 756 participants (M = 57.4, SD = 4.21; 57.7% NLB, 27.6% Latinx) underwent PET imaging with Florbetaben (FBB); amyloid positivity was defined by an SUVR of 1.08. Chi‐square tests were computed to examine associations across ethnocultural groups (i.e., NLB, Latinx, and NLW) and neurocognitive diagnoses, amyloid positivity, and psychiatric symptoms.

Results

The NLB group had significantly higher rates of MCI and lower rates of CU based on consensus diagnoses (n = 451; MCI = 30.6%, CU = 63.2%), compared to NLW (n = 389; MCI = 14.1%; CU = 80.7%, X2
= 41.20, p<.001) and Latinx groups (n = 722; MCI = 18.6%; CU = 76.2%, X2
= 40.09, p<.001). The NLB group also had higher rates of psychiatric symptoms, including mood changes (X2
= 17.70, p<.001), anxiety/nervousness (X2
= 13.05, p = .001), and aggression/irritability (X2
= 15.29, p<.001) compared to NLW and Latinx groups. In contrast, amyloid positivity and dementia rates did not significantly differ across groups (all ps>.05).

Conclusion

Young NLB participants in HABS‐HD had increased rates of MCI and psychiatric symptoms compared to NLW and Latinx participants. Also notable, there were no significant ethnocultural differences in amyloid positivity or dementia diagnosis. These patterns differ from those previously documented in primarily NLW samples, suggesting that psychosocial and possibly sociocultural factors may differentially affect cognitive health outcomes among middle‐aged NLB adults. Future research, with deeper sociocultural phenotyping, may help elucidate the potential mechanisms driving these differences.
A pilot study evaluating the feasibility, safety, and efficacy of transcranial photobiomodulation (tPBM) for the treatment of mild cognitive impairment (MCI): preliminary findings
Authors: Rashidi‐Ranjbar Neda , Churchill Nathan W. , Graham Simon J. , Schneider Raphael , Rajji Tarek K. , Andreazza Ana C. , Lim Lew , Coull Jeff , Munoz David G. , Fornazzari Luis R , Schweizer Tom A. , Fischer Corinne E.
Published: January 2025

Background

Mild Cognitive Impairment (MCI) is often a precursor to Alzheimer’s dementia (AD). Recent research underscores the relationship between mitochondrial dysfunction and amyloid‐beta accumulation, raising the prospect of targeting mitochondrial function for intervention. Transcranial photobiomodulation (tPBM), a non‐invasive technique utilizing near‐infrared light, has been shown to enhance mitochondrial function. Therefore, our study aimed to investigate the efficacy of tPBM in improving brain functions in MCI.

Methods

Fourteen (N = 14) participants with MCI recruited at St. Michael’s Hospital Memory Disorders Clinic were randomized (1:1) to either active or sham tPBM (Neuro RX Gamma, Vielight Inc). Participants underwent daily home‐based active or sham tPBM sessions over 6 weeks. Pre‐ and post‐treatment assessments included a comprehensive battery of tests, encompassing the Trail Making Test (TMT B & A), Mini‐Mental State Examination (MMSE), Proton Magnetic Resonance Spectroscopy (H‐MRS) of the posterior cingulate cortex, structural MRI, resting‐state functional MRI (rsfMRI), and blood‐based biomarker was collected using NMR spectroscopy quantitative and Neurology 3‐Plex A (N3PA) Assays.

Results

Comparing pre‐post changes in the active vs. sham group, we found significant differences favoring the active group (p’s<0.05) in: completing TMT‐B (t‐statistic = ‐2.1); for H‐MRS, decline in N‐acetyl aspartate to total creatine ratio (NAA/Cr) (t‐statistic = 2.8); increase in right thalamic volume (t‐statistic = 3.2); for rsfMRI, higher absolute change in functional connectivity in the default mode network (DMN) (t‐statistic = 3.5) and limbic network (t‐ statistic = 3.3), and between DMN and executive control network (ECN) (t‐statistic = 2.8); for blood results, decrease in isoleucine (t‐statistic = 3.0), methionine (t‐statistic = 3.1), and sarcosine (t‐statistic = 3.2) levels—markers linked to AD and amyloid plaque formation; and increase in butyrate (t‐statistic = ‐2.5) and L‐carnitine (t‐statistic = ‐2.6) levels—markers indicative of improved mitochondrial function. Furthermore, a notable trend was observed towards improved TMT B/A (p = 0.05, t‐statistic = ‐2.2) and MMSE (p = 0.06, t‐statistic = 2.0). Although the reduction in plasma tau levels within the active group was not statistically significant, it was notable (t‐statistic = 1.8).

Conclusions

Our pilot study suggests that tPBM could improve executive function, neuronal health, functional connectivity, and mitochondrial function, and decrease AD markers in patients with MCI. Further research with larger sample sizes is essential to replicate and validate these results.
Impact of beta‐amyloid oligomers on in vivo brain glucose metabolism
Authors: da Rocha Andreia Silva , Fontana Igor C. , Peixoto Guilherme G. Schu , Souza Amanda S , Venturin Gianina Teribele , Greggio Samuel , Forny‐Germano Leticia , Lourenco Mychael V , Rosa‐Neto Pedro , Souza Diogo O. , da Costa Jaderson Costa , Ferreira Sergio T , Zimmer Eduardo R.
Published: January 2025

Background

The deposition of β‐amyloid (Aβ) plaques is a classical neuropathological feature of Alzheimer’s disease (AD). Currently, it is believed that intermediate products of the Aβ fibrillogenesis process, like the β‐amyloid oligomers (AβOs), are the most toxic forms, and are involved in neurodegenerative processes in AD. The evaluation of cerebral glucose metabolism in patients with β‐amyloid plaque deposition using [18F]FDG‐PET has been used as a marker of neurodegeneration in AD. However, little is understood about AβOs' impact on glucose metabolism prior to Aβ plaques formation. The aim of this study was to evaluate the impact of the intracerebroventricular infusion of AβOs on in vivo glucose metabolism via [18F]FDG‐PET.

Method

Male Swiss mice (3‐month‐old, n = 20 per group) were divided into three groups: Vehicle, AβOs 10pmol, and AβOs 100pmol. Vehicle/AβOs were infused into mice’ right ventricle using the freehand technique after brief isoflurane anesthesia. [18F]FDG‐PET scans were performed 24h after AβOs infusion. The same animals underwent the Novel Object Recognition (NOR) task 24h after scanning. The images were processed and analyzed using MINC tools. Metabolic networks were built by computing Pearson correlation coefficients based on 2,000 bootstrap samples and FDR corrected (P<0.05). See Fig. 1a, for a experimental design illustration.

Results

AβOs induced dose‐dependent brain glucose hypometabolism (Fig. 1b) and metabolic network disturbances. Voxel‐wise percentage change analysis revealed moderate reductions in glucose brain metabolism (5% to 15%) following infusion of 10pmol AβOs, whereas 100 pmol AβOs led to widespread and substantial reductions of up to 25% (Fig. 1c). T‐statistical voxel‐wise analysis indicated statistically significant brain glucose hypometabolism only in the 100pmol group (Fig. 1d). The low‐dose AβOs (10pmol) induced brain inter‐region metabolic hyperconnectivity, while the 100 pmol dose caused hypoconnectivity (Fig. 1e). Furthermore, both AβOs infusion groups exhibited impaired recognition memory in the NOR task (Fig. 1f).

Conclusion

Our results are the first demonstration of AβOs causing in vivo glucose hypometabolism and metabolic network disturbances in the absence of plaques. These findings point to an early impact of AβOs on glucose metabolism, independent of β‐amyloid plaque formation. While the molecular pathways underlying this effect require further investigation, they may represent important AD pathophysiological mechanisms and potential targets for therapeutic intervention.
Prognostic Significance of Visit‐to‐visit Blood Pressure Variability for Cognitive Outcomes, Vascular Events, and All‐Cause Mortality in a Memory‐Clinic Cohort
Authors: Cui Jiangbo , Hilal Saima , Chen Christopher
Published: January 2025

Background

The clinical relevance of visit‐to‐visit blood pressure variability (BPV) remains unclear in the memory‐clinic setting. We aimed to investigate the prognostic significance of BPV for cognitive outcomes, vascular events, and all‐cause mortality in a memory‐clinic population.

Method

The study included 590 participants from an ongoing longitudinal memory clinic study who had ≥ 3 annual visits and a baseline MRI scan. Cognitive decline was defined as an annual increase of 0.5, 1, and 2 in the Clinical Dementia Rating sum of boxes for participants with No Cognitive impairment (NCI), Cognitive Impairment No Dementia (CIND), and dementia, respectively. Incident dementia was identified as transition from NCI or CIND to dementia. Incident vascular event was characterized as occurrence of cardiovascular disease, transient ischemic attack, or stroke. Significant cerebrovascular disease (sCeVD) was defined by MRI visual grading, and medial temporal lobe atrophy score ≥2 indicated neurodegeneration. Time‐dependent joint models were used, adjusting for mean BP, sCeVD, neurodegeneration, and other confounding factors, and accounting for mortality as a competing risk when necessary.

Result

Over a mean (SD) follow‐up of 3.28 (1.12) years after the second BP measurement, 294 cases of cognitive decline, 75 cases of incident dementia, 34 vascular events, and 59 cases of all‐cause mortality were recorded. Per 1‐SD increase in systolic BPV (SBPV) is associated with a higher risk of cognitive decline (HR: 1.03, 95% CI: 1.00 to 1.05, p = 0.021) and a higher risk of dementia (HR: 1.09, 95% CI: 1.02 to 1.15, p = 0.002). Subgroup analyses showed that association of SBPV with cognitive decline was significant in dementia‐free participants but non‐significant in those with dementia. These associations remained significant after adjusting for sCeVD and neurodegeneration. Increased SBPV was also associated with all‐cause mortality (HR: 1.08, 95% CI: 1.03 to 1.13, p = 0.006), but not with vascular events. Similar findings were observed with diastolic BPV.

Conclusion

Increased visit‐to‐visit BPV was associated with cognitive decline independent of mean BP, sCeVD and neurodegeneration among non‐demented older adults. Our findings suggest BPV may be a modifiable risk factor for adverse events and provide prognostic insights beyond mean BP in memory clinics.
Neurofibrillary tangle characterization in the olfactory bulb among clinicopathologic subtypes of Alzheimer’s disease
Authors: Chalk Jessica L , Kwan Rain , Martin Nicholas B , Moloney Christina M. , Boon Baayla D.C. , Dunlop Sara R , Rothberg Darren M. , Wood Ashley C. , Tranovich Jessica F. , Duara Ranjan , Graff‐Radford Neill R , Dickson Dennis W. , Murray Melissa E.
Published: January 2025

Background

Alzheimer’s disease (AD) is neuropathologically heterogeneous and can be objectively classified along a spectrum of corticolimbic tangle distribution as hippocampal sparing (HpSp) AD, typical AD, and limbic predominant AD. The olfactory bulb is an early area of tau accumulation with a direct connection to the amygdala. Although tau pathology has been identified in the olfactory bulb, its association with AD subtypes remains unclear. To investigate these differences, tau markers were characterized within the olfactory bulb among AD subtypes.

Method

The cohort included 39 AD cases (HpSp AD: n = 15, typical AD: n = 12, limbic AD: n = 12). Immunofluorescence staining was conducted on 5 µm thick formalin‐fixed paraffin‐embedded olfactory bulb sections using phosphorylated tau (AT8 & PHF‐1) and C‐terminal tau (2E9) antibodies. Slides were digitally scanned on the PhenoImager™ HT slide scanner and analyzed using QuPath Digital Analysis software, quantifying tau burden as a percentage of positive staining.

Result

In whole olfactory bulbs, AT8 was observed as intrasomal tangle‐like immunoreactivity with some extrasomal neuritic staining. AT8 burden did not differ among subtypes (HpSp AD median = 0.28% [interquartile range 0.014‐1.7%], typical AD = 0.28% [0.027‐2.24%], limbic AD = 0.39% [interquartile range 0.39‐0.74%]). PHF‐1 was observed as intrasomal tangle‐like immunoreactivity with abundant extrasomal neuritic pathology. PHF‐1 was observed to be highest in limbic AD (HpSp AD = 3.5% [0.63‐11%)], typical AD = 3.2% [0.38‐13%], and limbic AD = 5.3% [1.97‐10%]) and differed from typical AD (p<0.05). 2E9 was observed as intrasomal tangle‐like immunoreactivity with minimal extrasomal staining and not found to differ among subtypes (HpSp AD = 0.18% [0.036‐2.2%], typical AD = 0.15% [0.021‐2.4%], and limbic AD = 0.29% [0.0030‐8.2%]).

Conclusion

Abundant tau accumulation was observed among all AD subtypes with some suggestion of higher tau burden in limbic predominant AD. Given the direct connection between olfactory bulb and amygdala, it is interesting to speculate of an environmental contribution to limbic predominant AD through olfactory bulb damage. Future studies will expand the cohort to include AD cases with Lewy body disease co‐pathology and primary tauopathies with a focus on the anterior olfactory nucleus as the primary site of tau pathology.
Percentile‐based hippocampal volume MRI biomarker for distinguishing concomitant LATE and AD from pure LATE and pure AD
Authors: Mundada Nidhi S. , Lyu Xueying , McGrew Emily , Xie Long , Yushkevich Paul A. , Das Sandhitsu R. , Wolk David A
Published: January 2025

Background

Due to the lack of in vivo molecular biomarkers for Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), which commonly co‐occurs with Alzheimer’s disease (AD), it is challenging to identify patients with mixed AD/LATE pathology. Autopsy studies have suggested that AD patients with greater hippocampal atrophy are disproportionately enriched in having concomitant LATE. Here we define the lower quartile of hippocampal volume as a biomarker of possible LATE with AD.

Method

We identified 164 cognitively impaired participants from ADNI who had structural MRI, amyloid‐PET, and tau‐PET within 365 days. Patients were grouped based on hippocampal volume quartiles (adjusted for age and intracranial volume) and amyloid‐PET‐status into suspected 1) AD‐only (volume>50th‐percentile, amyloid‐positive), n = 100, 2) LATE‐only (volume<25th‐percentile, amyloid‐negative), n = 14, 3) AD+LATE (volume<25th‐percentile, amyloid‐positive), n = 50. 250 cognitively normal, amyloid‐negative participants were also included. Patterns of atrophy were examined to assess whether the AD+LATE group had features suggestive of LATE beyond hippocampal atrophy.

Result

Suspected‐AD+LATE group had lower MMSE, CDR, and hippocampal volume and higher ITG‐tau‐SUVR compared to the suspected‐AD‐only group (Figure‐1A). Suspected‐AD‐only group showed predominant posterior hippocampal atrophy whereas LATE showed a more severe anterior hippocampal atrophy (Figure‐1B/2B). When compared to the AD‐only group, suspected LATE‐only and AD+LATE groups showed significantly lower thickness in ERC, PHC, BA35, BA36 (Figure‐2A); there were no differences between LATE‐only and AD+LATE groups. Suspected‐AD+LATE group showed features suggestive of LATE in prior work (Figure‐2B). Whole brain analysis demonstrated that in comparison to controls the suspected‐AD‐only group showed lower thickness in typical AD regions (posterior hippocampus and temporoparietal regions), suspected‐LATE‐only group showed lower thickness in more anterior MTL regions including temporal pole consistent with LATE pathology, whereas suspected‐AD+LATE group showed lower thickness in both AD‐ and LATE‐like regions (Figure‐3A). Assessing neurodegeneration driven due to non‐tau factors by controlling for ITG‐tau‐SUVR revealed similar atrophy patterns for both suspected LATE‐only and AD+LATE groups compared to the AD‐only group. Both groups showed decreased thickness isolated to anterior hippocampus extending into temporal pole (Figure‐3B).

Conclusion

Using a simple hippocampal volume percentile‐based metric may enrich in patients with concomitant LATE on the AD continuum and could potentially be examined in the context of clinical trials and anti‐amyloid therapies.
Associations between deep category fluency phenotyping and early tau aggregation in the medial temporal lobe
Authors: Quenon Lisa , Leroy Emmanuelle , Clec'H Mélanie Le , Scemama Eva , Huyghe Lara , Colmant Lise , Salman Yasmine , Gérard Thomas , Malotaux Vincent , Dricot Laurence , Lhommel Renaud , Ivanoiu Adrian , Hanseeuw Bernard J
Published: January 2025

Background

Semantic processing relies on temporal brain regions, including medial temporal lobe (MTL) structures, that are the first to be affected by tau pathology in Alzheimer’s disease (AD). A widely used task to assess semantic memory is the category fluency. Performance on this task was demonstrated to be impaired since the prodromal stage of AD and associated to the structural integrity of the MTL. However, the associations between category fluency measures and MTL tau burden have been rarely explored at the early stages of the disease.

Method

Seventy‐five participants underwent [18F]MK6240 tau‐PET, magnetic resonance imaging and cognitive assessment including category fluency (animals, 2 minutes). Amyloid‐b (Ab) status was determined with lumbar punction or [18F]Flutemetamol Aβ‐PET (Ab+ for cerebrospinal fluid Ab level<437pg/ml or Centiloid≥20). Participants included 33 Ab‐ cognitively normal (CN), 15 Ab+ CN and 27 Ab+ MCI individuals (Table 1). In addition to the category fluency total score, the mean cluster size (cluster = group of words that are sequentially produced and all contained within a subcategory such as birds), the number of subcategories evoked (aggregating semantically related clusters), the mean size of subcategories and the number of switches between clusters were calculated. Associations between these metrics and MTL tau burden were assessed using Spearman‐rank coefficients and generalized linear models adjusting for age, sex and education.

Result

Over the entire sample, associations were found between the MTL tau burden and the total score (rs = ‐0.44, p<.001, Figure 1), the mean cluster size (rs = ‐0.29, p = .047), and the mean size of subcategories (rs = ‐0.40, p = .002), even when controlling for age, sex and education (b = ‐5.06, SE = 1.62, p = .003; b = ‐0.33, SE = 0.16, p = .039; b = ‐0.46, SE = 0.15, p = .003, respectively). The number of switches (rs = ‐0.13, p = 1.0) and the number of subcategories (rs = ‐0.13, p = 1.0) were not associated to the MTL tau burden.

Conclusion

MTL tau burden was equivalently associated to the category fluency total score and two metrics relying more purely on semantic memory (mean size of clusters and subcategories). Given its critical role in conceptual knowledge and its involvement in the earliest stage of tauopathy, future work will analyze the associations between tau burden in the (peri)rhinal cortex and the category fluency metrics.
Advanced Imaging Modalities for ARIA Detection and Treatment Efficacy Monitoring in Lecanemab Therapy for Alzheimer’s Disease: A Collaborative Prospective Study
Authors: Okafor Jude‐Patrick Nnamdi , Stefanko Jacob , Jana Nayid , McCullough Austin A. , Jarman Stephen , Banks Jessica N , Joseph‐Mathurin Nelly , Knopp Edmond , Benzinger Tammie L.S.
Published: January 2025

Background

Alzheimer’s disease (AD) poses a substantial healthcare challenge. Current immunotherapy targeting beta‐amyloid (Aβ) while representing a significant advancement, may be accompanied by potential complications such as amyloid‐related imaging abnormalities (ARIA). ARIA monitoring via high‐field MRI encounters logistical hurdles, exacerbated by regulatory demands for frequent MRI surveillance. This study investigates the integration of a portable ultra‐low field MRI into AD patient monitoring during immunotherapy to optimize ARIA detection, overall workflow and treatment outcomes.

Method

This prospective observational study recruits clinical patients with mild cognitive impairment due to Alzheimer disease underlying evaluation and monitoring for anti‐amyloid monoclonal antibody therapy. Baseline pre‐therapy 3T MRI will serve as a reference for subsequent imaging assessments. Participants undergo Hyperfine Swoop MRI scans at 0.064 tesla alongside their baseline and subsequent sessions, encompassing T1‐weighted, T2‐weighted, FLAIR, and DWI‐ADC sequences.

Monitoring extends for 12 months after the initial clinic visit, enabling real‐time treatment response evaluation. Each participant will undergo ∼5 paired imaging visits, according to the therapy FDA label.

Result

Effectiveness of high‐field and low‐field longitudinal imaging sessions will be compared for detection and evaluation of moderate and severe ARIA‐E (edema). A randomized, blinded assessment approach will be used to evaluate differences in radiologist assessment and treatment plan between field strengths. Patient imaging workflow improvement will be assessed using a survey.

Conclusion

The Hyperfine Swoop MRI, with its portability and accessibility, shows promise as a cost‐effective alternative to the standard 3T MRI with the significant value‐added benefit of optimization of workflow. Further research is needed to confirm these benefits in larger cohorts and assess long‐term reliability. Overall, our study highlights the potential of innovative imaging technologies in improving patient care, monitoring neurodegenerative diseases thereby establishing a more equitable scheme for patient care.
Analysis of machine learning algorithms to aid in the diagnosis of early‐stage dementia
Authors: Carvalho Thiago , Santana Maira
Published: January 2025

Background

Dementia, including Alzheimer’s disease, represents a growing challenge for public health, with early diagnosis being crucial to delay or even prevent progression to more severe forms of dementia, allowing individuals to maintain a healthy life for as long as possible. It also enables patients and their families to plan ahead for future care and needs. However, diagnosing in the pre‐dementia phase is quite challenging, as early symptoms can be subtle, and there is no single test that can definitively diagnose the disease; diagnosis is made through a combination of clinical evaluation, cognitive tests, and imaging exams. The use of machine learning algorithms emerges as a promising approach to identify diagnoses of mild cognitive impairment (MCI), offering the ability to identify complex patterns in patient data that may not be easily perceptible to healthcare professionals. Therefore, the aim of this study is to assess the performance of artificial intelligence algorithms in identifying early‐stage dementia from slices of magnetic resonance imaging represented by shape and texture features.

Method

To this end, an experiment was conducted using the Random Forest and Support Vector Machine (SVM) classification algorithms, carried out on a database composed of magnetic resonance images of 984 individuals, divided into three classes: Alzheimer’s disease, Mild Cognitive Impairment and Normal Cognition, with the intention of classifying among these three classes and attempting to predict which one a brain image would belong to.

Result

The results of the experiment revealed that SVM did not perform well, achieving a maximum accuracy of only 23.65%, regardless of the configuration used. On the other hand, Random Forest demonstrated promising performance, reaching a maximum accuracy of 56.08% with 150 trees.

Conclusion

However, it is important to note that despite the progress made, there are still significant challenges to be overcome in the quest for accurate and reliable methods for early diagnosis of dementia through magnetic resonance imaging.