bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel amyloid MRI imaging based on analysis of texture features representing Aß aggregation
Authors: Tatewaki Yasuko , Yamagata Hitoshi , Thyreau Benjamin , Yoneda Tetsuya , Nakase Taizen , Asato Momoka , Nagasaka Tatsuo , Kaneko Naoki , Hinman Jason , Taki Yasuyuki
Published: January 2025

Background

The importance of detecting amyloid β (Aβ) in the early stages of Alzheimer's disease has markedly increased following the approval of Lecanemab, a disease‐modifying drug. MRI is a non‐invasive and less expensive rather than amyloid PET as gold standard for Aβ biomarker, but its clinical ability to detect Aβ has not been demonstrated. MRI phase information reflects paramagnetic substance including iron associated with Aβ aggregation. We have developed a novel approach utilizing multi‐gradient echo (GRE) to perform texture analysis of the phase information, enabling visualization of Aβ. The primary aim of this study is to evaluate the diagnostic capabilities of this "Amyloid MRI" technique.

Method

The consecutive 48 participants (mean age: 72±10, mean MMSE: 25±4) who visited our memory clinic, and underwent both MRI and amyloid PET were enrolled. Amyloid PET images were visually interpreted as Aβ positive (n=30) or negative (n=18), and standardized uptake value ratio (SUVr) maps were generated. Multi‐GRE images were acquired with a 3‐Tesla MRI. We generated a phase slope map, i.e. a first‐order linear estimate of the phase change in time, and segmented four anatomical regions‐of‐interest (ROI) for cortex‐based analysis. Statistical analysis of texture features (mean, SD and entropy) derived from the phase slope map over each ROI was performed. We investigated the correlation between the mean value of regional SUVr and that of texture parameters of the phase slope map, and determined the optimal cut‐off of a linear classifier by ROC analysis based on the diagnosis of amyloid PET.

Result

The correlation coefficients between the mean value of SUVr and the texture features of the phase slope map in parietal, PCCpre, frontal and temporal were 0.57 (p<0.0001), 0.56 (p<0.0001), 0.48 (p<0.0006) and 0.22 (p<0.22), respectively. The optimal cut‐off values for diagnosing Aβ positive or negative showed a sensitivity of 83% (73‐93%), specificity of 89% (74‐103%) and accuracy of 85%(75‐96%).

Conclusion

The texture features of the phase slope map could reflect the spatial aggregation pattern of Aβ. Our method highlighted the potential to visualize Aβ using MRI.
Diagnostic challengein late onset CADASIL with atypical presentation‐case report
Authors: Romero Aury Stella Carrasquilla , Holguin Sergio Andres Taborda
Published: January 2025

Background

This study examines an exceptional case of CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a hereditary cerebrovascular disease caused by a mutation in the notch3 gene. In contrast to typical cases manifesting before the age of 50 with migraines, this report highlights an atypical presentation in a 70‐year‐old woman with no history of migraines nor cognitive impairment.

Method

The patient, with a history of type 2 diabetes, hypothyroidism, and dyslipidemia, was initially treated for cognitive impairment and behavioral changes under suspicion of autoimmune encephalitis. During outpatient follow‐up, the notch3 mutation was documented (Variant c.421c>T; p.Arg141Cys heterozygous NOTCH3 probably pathogenic Code 404841 GP) and confirmed through brain magnetic resonance imaging (MRI) consistent with CADASIL. The clinical examination included neuropsychological assessments and detailed genetic testing.

Result

The patient experienced rapid cognitive deterioration and behavioral changes, with temporary improvements following immunosuppressive treatments. However, complications arose, including pulmonary thromboembolism. Brain MRI revealed hyperintensity in the white matter of frontal and temporal lobes. Genetic analysis identified a probably pathogenic heterozygous variant in the notch3 gene

Conclusion

This case underscores the importance of considering CADASIL in atypical presentations, especially in older patients. Confirmation of the diagnosis through MRI and genetic analysis emphasizes the significance of these diagnostic tools. While proven therapies for improving the disease are lacking, the study highlights the relevance of comprehensive care and specialized follow‐up in CADASIL cases. It concludes with the need for further research in older adult populations to better understand the prevalence and evolution of the pathology in this demographic.
A trial of the iron‐chelator deferiprone in Alzheimer’s disease
Authors: Ayton Scott , Bush Ashley I. ,   3D trial investigators
Published: January 2025

Background

Iron is vital for metabolism but can act as a catalyst for oxidative damage. Elevated brain iron, determined from biomarkers of iron (CSF ferritin and quantitative susceptibility mapping MRI) and from post‐mortem measurement of brain iron, has been associated with accelerated cognitive decline in multiple Alzheimer’s disease (AD) clinical, cohorts. These findings supported the hypothesis that treatment with the brain‐permeable iron chelator deferiprone may be associated clinical benefit in AD.

Methods

A multicentre, phase II, double‐blind, randomized, placebo controlled clinical trial of deferiprone (15 mg/kg administered orally twice a day) was conducted in people with amyloid‐confirmed MCI and mild AD (MMSE≥20) over 12 months. The primary outcome was cognition, assessed at baseline, 6 months, 12 months using neuropsychological test battery of memory (3), executive function (3) and attention (2). Secondary outcomes included adverse events (safety analysis), change in brain iron burden measured by quantitative susceptibility mapping MRI (target engagement), and brain volume changes (secondary efficacy measure).

Results

81 participants were recruited and randomized in a 2:1 ratio (53 drug:28 placebo). Baseline characteristics were equivalent between arms. 54 participants completed the study (withdrawals = 7 placebo and 20 deferiprone arm). Quantitative susceptibility mapping of the hippocampus at baseline and 12 months confirmed a significant (β[95%CI]:‐6.7 [‐11.0,‐2.5]; P = 0.004) lowering of brain iron in the deferiprone arm (mean change:‐3.71 ppb, 95% CI:‐7.24, ‐0.18) compared to placebo, whose iron levels increased during this timeframe (+3.03 ppb, 95%CI: 0.27, 5.80). Participants in the Deferiprone arm showed large statistically significant cognitive decline (β[95%CI]:‐0.295 [‐0.456, ‐0.135], P<0.001, Cohen’s d: ‐0.704) compared to placebo (deferiprone mean change, [95%CI]:‐0.86, [‐1.12, ‐0.61]; placebo mean change, [95%CI]:‐0.27, [‐0.55, 0.00]).

Conclusion

Deferiprone (30 mg/kg/day) treatment markedly accelerated cognitive decline in people with amyloid‐confirmed MCI and mild AD. These findings highlight the importance of iron for cognition in AD, and provoke new questions. It is possible that iron elevation in AD is protective, or represents iron being sequestered inappropriately (e.g. deposited in pathology) leading to functional iron deficiency; or the chosen dose of deferiprone was too high for this condition.
Plasma Biomarkers for Accelerated Cognitive Decline: A Tool for Targeted Clinical Trial Recruitment
Authors: Anastasi Federica , Escalante Armand González , Segura‐Retana Pol , Ortiz‐Romero Paula , López‐Martos David , Sánchez‐Benavides Gonzalo , Minguillon Carolina , del Campo Marta , Suarez‐Calvet Marc
Published: January 2025

Background

Detecting Alzheimer's disease (AD) biological hallmarks before clinical symptoms emerge is now possible with available blood‐based biomarkers. However, the rate of cognitive decline varies among individuals at risk of AD, and accurate prognostic blood‐based biomarkers are lacking. Our goal is to identify plasma proteins predictive of fast cognitive decline in asymptomatic individuals at risk of AD.

Method

We studied 93 cognitively unimpaired individuals from the ALFA+ cohort with two longitudinal cognitive assessments (3‐year follow‐up, Preclinical Alzheimer Cognitive Composite, PACC). PACC‐changes were calculated as the change in PACC scores between two visits divided by the time elapsed. Adjustments for demographic variables associated with PACC‐change (age and education years) were made by residualizing. Two groups were defined based on residual median values, namely the slow‐ and the fast‐cognitive decliners groups. Protein levels in plasma were measured using Proximity Extension Assay (PEA) technology (Olink).

Result

In a preliminary analysis, non‐parametric univariate analysis of baseline proteomics data identified 74 significantly different proteins between slow‐ and fast‐cognitive decliners. Specifically, 29 proteins were upregulated in fast decliners, and 45 in slow decliners, with the latter enriched in REACTOME Pathways of Cytokine Signalling and Immune System. Synaptic proteins were among the most significantly deregulated.

Conclusion

Plasma protein signatures at baseline differ between individuals with fast and slow rates of cognitive decline. Early identification of those with rapid disease progression is crucial for efficient clinical trial recruitment. Faster cognitive decline can shorten testing periods, enhancing trial efficiency and expediting the assessment of potential interventions.
Discriminating between native and phosphorylated tau proteins using fluid‐lipid bilayer‐coated nanopores
Authors: Awasthi Saurabh , Mayer Michael
Published: January 2025

Background

Tau protein phosphorylation and aggregation are the pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. Multiple phosphorylation sites in Tau protein at serine (S), threonine (T), and tyrosine result in high heterogeneity and enhanced aggregation kinetics.

Method

Here, we used nanopores coated with a fluid lipid bilayer to characterize native and hyperphosphorylated Tau proteins on a single‐molecule level.

Result

Single‐molecule level analysis determines the size, shape, net charge, and dipole moment of individual tau protein monomers. The approach makes it possible to differentiate native and hyperphosphorylated Tau proteins based on their net charge. Moreover, single‐particle size analysis revealed the spontaneous formation of low‐n oligomers such as dimer, trimer, tetramer and pentamers; no other molecules were needed to initiate aggregation to these oligomers.

Conclusion

The nanopore‐based approach enables discrimination of native and hyperphosphorylated Tau proteins based on their net charge. Furthermore, single‐particle size approximation is helpful for detecting early‐stage aggregation of Tau and characterization of various oligomer species.
Assessing of the glymphatic system using DTI‐ALPS MRI in patients with neurodegenerative diseases
Authors: Liaskovik Alina , Fedotova Ekaterina , Konovalov Rodion , Krotenkova Marina V. , Shpilyukova Yuliya , Nevzorova Kseniya , Brsikyan Lusine
Published: January 2025

Background

Dysfunction of the glymphatic system (GS), a recently discovered brain by‐product elimination system, is considered to be one of the pathophysiological mechanisms for common neurodegenerative diseases such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In 2017 a new way to assess the GS was proposed – a diffusion tensor images analysis along perivascular spaces (DTI‐ALPS).

In our work we evaluated the DTI‐ALPS index in groups of patients with AD, DLB, PD and in a comparison group of patients with normal pressure hydrocephalus (NPH).

Methods

We examined 32 patients diagnosed with AD [69.5±8.0 years], 15 patients with DLB [71.1±8.0 years], 31 patients with PD without dementia [64.0±6.9 years], 11 patients NPH [68.5±9.8 years] and 27 healthy controls [63.2±7.0 years]. In four patient groups cognitive impairment was rated with Montreal Cognitive Assessment scale (MоCA).

The diffusion images were acquired on a SIEMENS Prisma scanner using a 2D EPI diffusion sequence. TE=82 ms, TR=5600 ms. The b‐values were 1000 and 2500 s/mm². The number of diffusion sampling directions were 64 and 64, respectively. The slice thickness was 2 mm.

Post‐processing steps were performed using DSI studio software. Next, we identified ROIs corresponding to projection and associative fibers with further extraction of tensor values in the directions Dxx, Dyy, Dzz, which were entered into a table to calculate the DTI‐ALPS index using formula ALPS‐index=mean(Dxxproj+Dxxassoci)/mean(Dyyproj+Dzzassoci) for further statistical processing.

Results

Patients with AD, DLB and NPH had a significantly lower values of DTI‐ALPS index on both sides compared to healthy volunteers (p<0.001). The differences between PD and healthy controls turned out to be statistically insignificant.

In addition, analysis of all the patients revealed a significant direct correlation between the MoCA score and DTI‐ALPS values on both sides (pL=0.002; pR=0.035).

Conclusion

The obtained results showed that the glymphatic dysfunction assessed by DTI‐ALPS index could be considered as a possible participant in the pathogenesis of AD and DLB as well as in NPH reflecting cognitive decline. Whereas the glymphatic dysfunction in PD was not confirmed.
Improving access to dementia care community resources in the Pacific island of Guam
Authors: Twaddle Iain K. B. , Gutierrez Nikolas Jude , Saloma Maree Josephine , Maestrecampo Camille Minerva
Published: January 2025

The island of Guam is a U.S. territory in the Western Pacific with a population of approximately 174,000. Most persons with Alzheimer’s disease and related dementias (ADRD) in Guam live at home with their family. This is due, in part, to Guam’s indigenous Chamorro culture, which emphasizes the importance of caring for the manåmko’ (elderly), but also to the limited availability of residential care facilities for older adults. In fact, Guam currently has no nursing homes or assisted living facilities that specialize in care for persons living with ADRD. This places a heavy burden on Guam’s families. Fortunately, Guam has an impressive array of community‐based resources to support persons living with dementia and their family caregivers. However, many members of the community are not aware of these services or do not know how to access them. To improve access to Guam’s dementia care support services, a series of education outreach presentations were provided to the community through an online support group for family caregivers of persons with dementia held weekly on Wednesday evenings and Saturday mornings. The presentations were conducted by elder care specialists from local government agencies and private healthcare organizations. A wide range of services were covered including: (1) adult day care services; (2) transportation services; (3) congregate and home‐delivered meals; (4) adult protective services; (5) case management services; (6) in‐home services; (7) home health services; (8) long‐term residential care for non‐ambulatory older adults; (9) government health insurance programs for older adults including Medicaid and Guam’s Medically Indigent Program; and (10) legal services for older adults, including guardianship, powers of attorney, wills, living wills, and advance healthcare directives. Each presentation provided guidance on eligibility criteria and application procedures, as well as contact information for key personnel. Program outcomes indicate the following: (1) all sessions were well attended; (2) participant feedback was overwhelmingly positive; and (3) a significant number of participants followed through with applying for dementia care services. In sum, education outreach presentations conducted online can serve as an effective means to improve access to community resources for persons living with ADRD and their family caregivers.
BrainChart hippocampal volume age, sex and TIV adjusted centile scores in Alzheimer’s disease
Authors: Parker Thomas D , Bethlehem Richard A.I. , Seidlitz Jakob , White Simon R , Dorfschmidt Lena , Bernstock Joshua D , Bourke Niall , David Michael CB , de Taurines Anastasia Francoise L Gailly , Giovane Martina Del , Graham Neil SN , Kolanko Magdalena A. , Zimmerman Karl A , Malhotra Paresh , Patel Maneesh , Scott Gregory PT , Alexander‐Bloch Aaron , Bullmore Edward T , Sharp David J
Published: January 2025

Background

The hippocampus is a key site of atrophy in Alzheimer’s disease (AD) and MRI derived estimates of hippocampal volume have been shown to be a robust biomarker of AD‐related neurodegeneration. However, its application at the individual level is limited by the lack of reference standards from large normative datasets that can be applied across a wide range of settings. We aimed to investigate the utility of hippocampal volume centile scores adjusted for age, sex and total intracranial volume (TIV) derived from a normative data from 101,457 participants across the life course, as a biomarker of neurodegeneration in AD.

Methods

BrainChart calculates age and sex adjusted centile scores for structural MRI metrics using a GAMLSS (Generalised Additive Models for Location Scale and Shape) approach and can be applied to individual datasets using an out‐of‐sample centile scoring approach that calculates study‐specific offsets (Bethlehem, Seidlitz, White et al. Nature 2022). Using this approach, we developed models for Freesurfer derived estimates of hippocampal volume additionally incorporating TIV as a co‐variate. This was then applied to 351 individuals with pathologically confirmed AD (median scan time prior to death 5.9 years) from the NACC dataset, as well as 110 amyloid‐PET positive patients from the ADNI‐3 cohort (MCI n=71, AD dementia n=39). Wilcoxon rank‐sum tests were used to assess differences between patient groups and cognitively normal controls from the relevant datasets. Spearman’s rank correlations were used to assess relationships with cognition (MMSE score).

Results

Median centile scores were reduced in all patient groups (pathologically confirmed AD cases left = 0.13, right =0.13; amyloid‐PET positive MCI cases left=0.12, right=0.16; and amyloid‐PET positive AD dementia left=0.01, right=0.02). This was significantly different to cognitively normal controls from both the NACC dataset (n=1400, cases left=0.52, right=0.52) and ADNI‐3 dataset (n=247, cases left=0.50, right=0.50), all to a significance level of p<0.0001. Hippocampal centile scores strongly predicted MMSE score in both cohorts (Spearmans’ Rho range 0.37‐0.41, p<0.001).

Conclusion

BrainChart age, sex and TIV adjusted hippocampal volume centile scores, derived from an extensive normative dataset, represent a method for objectively identifying neurodegeneration in AD that is interpretable at the individual level.
Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease
Authors: Caro Ilana , Western Daniel , Okada Yukinori , Jager Philip L. De , Duperron Marie‐Gabrielle , Sargurupremraj Muralidharan , Seshadri Sudha , Tregouët David Alexandre , Cruchaga Carlos , Debette Stéphanie ,   neuroCHARGE
Published: January 2025

Background

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Its underlying mechanisms remain elusive and specific mechanism‐based drugs are lacking.

Method

We integrated more than 2,800 CSF and 4,600 plasma pQTL, derived from the largest proteomic studies so far (SOMAscan 7k and 4k; in up to 35,559 individuals), and the two most prevalent MRI‐markers of cSVD (MRI‐cSVD, white matter hyperintensities and perivascular spaces burden; in up to 48,454 individuals) in a Mendelian Randomization (MR) framework to identify causal and druggable targets for cSVD. Identified association were followed‐up using a multipronged approach: across fluids, proteomics platforms (Olink 3072, N=8,590) and lifespan (N=1,748), using both MR and individual‐level data.

Result

We found 51 proteins associated with MRI‐cSVD of which 46 in CSF and 9 in plasma. Among available significant CSF‐ and plasma‐proteins, 32% and 31% replicated in cross‐fluid and cross‐platform follow‐up, and 47% were associated with stroke and/or dementia at least at nominal significance. We found converging evidence that protein‐cSVD associations are enriched in extracellular matrix and immune response pathways. Immunity‐related proteins already showed association with MRI‐cSVD already in young adults in their twenties. Furthermore, we provide genetic support for drug repositioning opportunities for cSVD, including compounds crossing the blood brain barrier.

Conclusion

Together, these findings provide a novel proteogenomic signature of cSVD and pave the way for novel therapeutic developments.
Increased blood‐brain barrier permeability following COVID‐19 and its correlation with Alzheimer’s biomarkers
Authors: Sun Zhe , Frontera Jennifer , Masurkar Arjun V. , Boutajangout Allal , Jiang Li , Thawani Sujata , Links Jon , Vedvyas Alok , Betensky Rebecca A , Debure Ludovic , Ahmed Wajiha , Wisniewski Thomas , Ge Yulin
Published: January 2025

Background

Post‐COVID cognitive dysfunctions, impacting attention, memory, and learning, might be linked to inflammation‐induced blood‐brain barrier (BBB) impairment. This study explores post‐COVID BBB permeability changes using a non‐contrast water‐exchange based MRI and their associations with blood Alzheimer’s biomarkers.

Method

Sixty‐seven participants were classified based on COVID (COV) and cognitive (COG) statuses into three groups: COV+/COG‐ (n=34), COV+/COG+ (n=23), and COV‐ (n=10) for comparisons (COV+: Laboratory‐verified SARS‐CoV‐2 infection; COV‐: No history of SARS‐CoV‐2 infection and negative SARS‐CoV‐2 nucleocapsid antibody test.). All patients underwent neuropsychological testing and were coded as having cognitive impairment (COG+) based on neuropsychological testing (≥1 abnormal test result). Clinician interview with the patient and informant. Patients were imaged with the following 3T‐MRI sequences: 1) T1‐MPRAGE; 2) Phase contrast (PC)‐MRI for quantification of cerebral blood flow (ƒ). 3) Water‐extraction‐with‐phase‐contrast‐arterial‐spin‐tagging (WEPCAST) [1], estimating permeability‐surface‐area‐product (PS) calculated with Renkin‐Crone Model: PS = ‐ln (1‐E) ∗ƒ (Figure 1). Plasma biomarkers of Alzheimer’s disease (AD), including Aβ40, Aβ42, NFL, and pTau181, were measured on the same day as the MRI. PS was compared between groups. Correlations were computed between PS and AD biomarkers.

Result

We included 67 non‐hospitalized participants (age: 64.7, F/M: 43/24) who successfully completed their clinical and MRI exams. Illustrative WEPCAST images and the results of group comparisons indicated that BBB permeability (PS) was higher in COV+ than that in COV‐ subjects (119 vs 96 mg/100 g/min, P=0.006), as well as in any patient with cognitive dysfunction (COG+ vs COG‐, 122 vs 111 mg/100 g/min, P=0.0319). Similarly, among COV+ subjects, PS was significantly higher in COV+COG+ compared to COV+COG‐ subjects (129 vs 113 mg/100 g/min, P=0.0041; Figure 2). After adjusting age, PS was negatively correlated with plasma Aβ42 (r=‐0.28, P=0.02), and positively correlated with pTau181 (r=0.24, P=0.046) in all subjects. (Figure 3). There was no significant correlation between PS and NLF or Aβ40.

Conclusion

Our findings demonstrate that SARS‐CoV‐2 virus has an impact on BBB integrity. This effect correlates with several AD biomarkers, including plasma Aβ42 and pTau181, highlighting the potential contribution of increased BBB permeability in post‐COVID to AD pathology.

Reference: 1. Lin Z, et al. Magn. Reson. Med. 2018;80:1507–1520.
Diagnostic and analytical performance of plasma pTau181 and 217 in a clinical laboratory
Authors: Mammel Anna , Hsiung Ging‐Yuek Robin , Encarnacion Mary , Hallett Kelsey , Biehl Donald , Mousavi Ali , Frykman Hans
Published: January 2025

Background

Blood‐based biomarkers will be essential for providing clinicians an accessible and cost‐effective Alzheimer’s disease (AD) screening tool. Elevated levels of two phosphorylated tau biomarkers (pTau181 & pTau217) correlated with amyloid and tau‐PET consistent with AD diagnosis. We evaluated the analytical and clinical performance of each biomarkers using two different high‐sensitivity methodologies (CLEIA and Simoa®) in a single laboratory to compare the performance of pTau181 and 217 in a clinical (CLIA‐certified) laboratory.

Method

Plasma pTau217 levels were measure using either the ALZpath pTau217 assay on the Quanterix HD‐X Simoa® platform or LUMIPULSE plasma pTau 217 on the Lumipulse G1200 platform. Plasma pTau181 levels were measured on the Simoa® platform using ADx Neurosciences antibodies.

Analytical performance including sensitivity, linearity, precision, accuracy, cross‐reactivity, interference, and sample stability was determined at Neurocode’s CLIA laboratory using CLIA guidelines.

Clinical testing was performed using a collection of amyloid PET confirmed samples (N = 260). And neuropathology confirmed samples collected from the University of British Columbia (UBC) at the time of initial diagnosis (N = 119).

Result

pTau217 (AUC – 0.92 to 0.93) had enhanced clinical performance compared to pTau181 across platforms (AUC 0.81) and sample cohorts for diagnosing AD. pTau217 assays had a greater dynamic range (i.e. lower limit quantification) compared to pTau181, resulting in more substantial separation between lower‐limits and clinical decision points. pTau217 has a higher fold difference between PET positive and negative subjects regardless of methodology compared to pTau181. Sample stability was comparable across platforms and methodology. Between lot precision of pTau217 (≤ 13% CV) was improved compared to pTau181 (≤ 20% CV) on the Simoa platform.

Conclusion

In conclusion, the superior clinical and analytical performance of pTau217 advocates for its use in clinical practice over pTau181. Plasma pTau217 is a robust screening tool that can be used by clinician for accurate and reliable Alzheimer's disease diagnosis.
The Centiloid scale: guidance on clinical context of use from the AMYPAD Consortium
Authors: Bollack Ariane , Collij Lyduine E. , Shekari Mahnaz , Bullich Santiago , Roé‐Vellvé Núria , Koglin Norman , Stephens Andrew W. , Battle Mark R , Buckley Christopher , Barkhof Frederik , Gispert Juan Domingo , Farrar Gill ,   the AMYPAD consortium
Published: January 2025

Background

The Centiloid method (CL) was introduced as a tracer‐independent measure for cortical amyloid load and is now commonly used in Alzheimer’s disease (AD) clinical trials. To facilitate its implementation into clinical settings, the AMYPAD consortium set out to integrate existing literature and recent work from the consortium to provide clinical context‐of‐use recommendations of the Centiloid scale, which has been submitted to the European Medicine Agency for endorsement as a Biomarker Qualification Opinion.

Method

Screening of the literature was performed on the 7/11/23 on PubMed to identify articles mentioning “Centiloid”. The 159 results were reviewed to identify all cut‐offs established based on histopathology, visual reads, fluid biomarkers and cognition. Clinical trials inclusion criteria and amyloid clearance strategies were also included.

Result

Compared to histopathology (gold standard), visual reads, and cerebrospinal fluid (clinical standards), Centiloid quantification accurately reflects the amount of AD pathology. With high certainty at the individual level, a CL value below 10 excludes the presence of Aβ pathology, while a value above 30 is a conservative estimate of amyloid‐positivity (Figure 1). Values falling in between these two cut‐offs (i.e., ‘gray‐zone’) are related to an increased risk of disease progression, but future studies enriched for this population are needed. The AMYPAD consortium additionally assessed the robustness and measurement uncertainty of the Centiloid scale and demonstrated that the method is highly robust against pipeline differences, such as processing space, target region, and reference region, though use of the pons could lead to increased bias and is not recommended. Measurement uncertainty was 3 to 8.3 CL across the total scale and is amyloid burden dependent.

Conclusion

Four clinical context‐of‐use for CL quantification are proposed: 1) adjunct to visual inspection methodology to achieve high certainty regarding the presence or absence of Aβ pathology, 2) a CL level of >30 could be utilised as a conservative cut‐off for the presence of Aβ pathology to guide the management of patients with objective cognitive impairment who may be eligible for anti‐amyloid disease‐modifying therapies, 3) support therapy monitoring and treatment decisions, 4) identification of emerging amyloid deposition and optimize risk‐stratification. Accounting for measurement uncertainty is essential when interpreting CL units.
Cerebrovascular reactivity as a candidate biomarker in small vessel disease related VCID
Authors: Lu Hanzhang
Published: January 2025

Background

The brain’s ability to perform a cognitive task is a dynamic process and requires small blood vessels to dilate or constrict in real time to adjust blood flow in a region‐specific manner. Cerebrovascular Reactivity (CVR) measures the ability of vessels to react to vasoactive challenges. In this work, we investigated the role of CVR as a possible biomarker in small vessel disease related vascular contributions to cognitive impairment and dementia (VCID), as part of the NINDS‐funded MarkVCID study.

Methods

This work consisted of 4 studies. CVR was measured by MRI signal changes in response to inhalation of 5% carbon dioxide (CO2) (Figure 1). Study 1 was a single‐site study of 72 participants (aged 69±8 years, 28 normal cognition and 44 cognitive impairment), in which we examined the relationship between CVR and cognitive function, CSF‐measured AD pathological markers, and CDR‐sum‐of‐boxes. Study 2 conducted an instrumental validation to benchmark the test‐retest reproducibility of the CVR measure. Study 3 developed an automatic, cloud‐based tool for automatic and standardized processing of CVR MRI data. Study 4 was a multi‐site biological validation study in which CVR was measured across 3 sites and data from each site were separately analyzed to investigate the relationship between CVR and cognitive function.

Results

Study 1 revealed that whole‐brain CVR was associated with MoCA (β=29.64, 95% CI, 9.94 to 49.34) and global composite scores (β=4.32, 95% CI, 0.05 to 8.58), and these associations were independent of CSF‐measured amyloid and tau markers. CVR was also associated with CDR‐SB score. Study 2 revealed that inter‐scanner CoV of CVR was 6.90 ± 5.08% and had an ICC of 0.8498. Study 3 showed that CVR processing can be standardized and the processing pipeline can be accessed by any researchers around the world through an installation‐free cloud platform referred to as MRICloud (https://braingps.mricloud.org/cvr.v5). Study 4 showed that CVR was significantly associated with MoCA in data analyzed separately in each of the three sites through a pre‐defined analysis (p=0.003, 0.002, 0.046 for the three sites, respectively; when pooling data together p=3.7*10^‐6) (Figure 2).

Conclusion

CVR measured with MRI is a promising candidate biomarker in VCID.
Interactions of VEGF 1154A and 2578C with APOE ε4 on Amyloid Load in Cognitively Unimpaired Older Adults
Authors: Malek‐Ahmadi Michael H. , Piras Ignazio , Wang Qi , Chen Kewei , Devadas Vivek , Luo Ji , Su Yi
Published: January 2025

Background

Previous studies have shown that carriage of the VEGF 1154A (rs1570360) and the VEGF 2578C (rs699947) alleles may confer a protective effect on the development of Alzheimer’s disease (AD). However, it is unknown if these associations are APOE‐dependent and whether they can be observed in asymptomatic individuals with varying levels of amyloid pathology. The aim of this study is to determine whether interactions between the APOE ε4 allele, VEGF 1154A, and VEGF 2578C are associated with amyloid load in cognitively unimpaired (CU) older adults.

Method

Data from 341 CU ADNI subjects (57% female) with a mean age of 74.35±6.94 years and a mean education level of 16.63±2.44 years were included in the analysis. Thirty‐two percent (n=109) were APOE ε4 carriers with the following distributions for each VEGF allele: 1154A – GG=165, AG=147, AA=29; 2578C – AA=88, AC=166, CC=87. AV‐45 mean cortical standard uptake value ratio (MCSUVR) was used to determine amyloid load. Generalized linear models were used to quantify the main effects of the VEGF alleles and their interactions with APOE ε4 on demographically‐adjusted MCSUVR values. Cohen’s d effect size was used for groupwise comparisons.

Result

The interaction between VEGF 1154A and APOE was statistically significant (β = ‐0.02, 95% CI (‐0.04, ‐0.008), p = 0.002). Further analysis among those with two A alleles of VEGF 1154 found that APOE ε4 carriers had substantially lower amyloid load relative to ε4 non‐carriers (p = 0.01, d = 1.04). Within APOE ε4 carriers, there were no significant differences among the GG, AG, and AA genotypes. The interaction for VEGF 2578C and APOE approached statistical significance for amyloid load (β = 0.01, 95% CI (‐0.001, 0.03), p = 0.06).

Conclusion

The AA genotype of VEGF 1154 is associated with reduced amyloid load in APOE ε4 carriers and warrants further investigation as a potential protective factor for AD.
The ARTS Marker of Arteriolosclerosis: Instrumental and Clinical Validation
Authors: Arfanakis Konstantions , Evia Arnold M , Leurgans Sue E. , Fornage Myriam , Lu Hanzhang , Arvind Caprihan , Decarli Charles , Gold Brian T , Maillard Pauline , Satizabal Claudia L , Stables Lara , Wang Danny JJ , Helmer Karl G , Fischl Bruce , Singh Herpreet , Schwab Kristin , Greenberg Steven M. , Schneider Julie A. ,   MarkVCID Consortium
Published: January 2025

Background

The ARTS biomarker is a fully automated software container that predicts the presence of arteriolosclerosis based on in‐vivo MRI data and demographic features. The present study describes findings from the instrumental and clinical validation of ARTS conducted by the MarkVCID consortium.

Method

Instrumental validation of ARTS involved assessment of inter‐rater reliability, test‐retest repeatability, and inter‐scanner reproducibility. Inter‐rater reliability was assessed by means of the intraclass correlation (ICC) between ARTS scores generated from all MarkVCID sites using data on 20 older adults. Test‐retest repeatability was assessed by means of the ICC between test and retest ARTS scores from 41 older adults imaged twice. Inter‐scanner reproducibility was assessed by means of the ICC between ARTS scores on 20 older adults imaged on 4 different scanners.

Clinical validation of ARTS included two groups of non‐demented older adults: N=156 participating in community cohort studies at Rush Alzheimer’s Disease Center; and N=906 participating in the Atherosclerosis Risk in Communities (ARIC) study. The primary prespecified hypothesis was that change in Trails B score (or perceptual speed score for Rush data) two years after baseline MRI is associated with baseline ARTS score, controlling for years of education. The secondary prespecified hypothesis was that baseline Trails B (or perceptual speed) is associated with baseline ARTS score, controlling for years of education.

Results

ARTS exhibited excellent inter‐rater reliability (ICC=0.9999, p<10‐200, CI:[0.99987, 0.99997]), test‐retest repeatability (ICC=0.996, p<10‐42, CI:[0.993, 0.998]), and inter‐scanner reproducibility (ICC=0.955, p=0.00018, CI:[0.622,0.989]). In Rush data, a higher baseline ARTS score was associated with a faster two‐year decline in perceptual speed (beta=‐0.32, p=0.04, CI:[‐0.63, ‐0.01]) (Figure 1A) and a lower baseline level of perceptual speed (beta=‐1.04, p<10‐4, CI:[‐1.48, ‐0.60]) (Figure 1B). In ARIC data, a higher baseline ARTS score was associated with a faster annual increase in Trails B (beta=3.7, SE=1.7, p=0.03) (Figure 2A), and a higher baseline Trails B (beta=45.5, SE=5.8, p<10‐4) (Figure 2B).

Conclusion

ARTS exhibited outstanding technical performance and baseline ARTS score was associated with subsequent decline in cognitive abilities known to be affected by small vessel disease. The above evidence supports ARTS as a marker of the risk of vascular contributions to cognitive impairment and dementia (VCID).
Examining the utility of plasma Alzheimer’s disease biomarkers across diverse populations
Authors: O'Bryant Sid E. , Petersen Melissa
Published: January 2025

Background

Plasma biomarkers of Alzheimer's disease were examined in the Health & Aging Brain Study ‐ Health Disparities (HABS‐HD). Data from n>3,000 participants (n>1,000 African American, n>1,000 Hispanic, n>1,000 non‐Hispanic white) were examined in relation to cognitive diagnoses, functional outcomes and imaging (MRI, PET amyloid and PET tau) outcomes.

Method

Plasma biomarkers were examined via single molecule assays using the Simoa technology. MRI was conducted using 3T Siemens scanner using ADNI protocols. PET amyloid (Neuraceq) and PET tau (PI2620) were captured using Siemens PET/CT scanners. All imaging data was examined using standardized pipelines at LONI.

Result

Plasma biomarkers of amyloid, tau and neurodegeneration vary by race/ethnicity. Plasma proteomic profiles were highly accurate in detecting MCI/dementia as well as amyloid positivity across race/ethnic groups; however, the protein importance plots varied across groups. Plasma biomarkers were also significantly associated with functional outcomes. Finally, measures of metabolic functioning were also associated with amyloid and tau outcomes, which varied by race/ethnic groups.

Conclusion

Plasma biomarkers can be used in multi‐step screening procedures for increasing inclusion in clinical research. Additionally, these biomarkers vary with regards to level and clinical impact across race and ethnic groups. Therefore, additional work is needed to understand plasma biomarkers across diverse populations in order to establish them as front‐line rule out screening tools.
Anosognosia and caregiver distress independently identify subjects at high risk of developing dementia of Alzheimer’s type
Authors: Pantazis Dimitrios , Medani Takfarinas , Joshi Anand A , Mahurkar‐Joshi Swapna , Leahy Richard , Andrade Katia
Published: January 2025

Background

It is estimated that up to 80% of people with Alzheimer’s disease (AD) may have some form of anosognosia. Anosognosia also constitutes a major source of stress for caregivers as it delays diagnosis and affects compliance with treatment. Here, we aimed to explore whether and how early anosognosia and caregiver burden could independently serve as indicators for identifying patients at risk of converting to AD.

Method

We analyzed data from 1473 participants enrolled in the ADNI longitudinal study. Participants were stratified into three distinct groups: the Mild Cognitive Impairment Conversion group (MCI Conv) comprising n=175 patients who progressed to AD during the study, the Mild Cognitive Impairment Stable group (MCI Stable) comprising n=531 patients who maintained stability throughout the study, and the Cognitive Normal group (CN) comprising n=767 individuals. For each individual and study visit, anosognosia assessment was based on the overall participant versus partner discrepancy score of the Everyday Cognition (ECog) scale. Caregiver burden was based on the Neuropsychiatric Inventory (NPI).

Result

We found that both anosognosia index and caregiver burden could robustly identify patients at risk of converting to AD (Figure 1). Anosognosia index was significantly more positive for the MCI Conv than the MCI Stable group as early as 48 months before conversion (t = 2.58, p = 0.0163, FDR‐adjusted). Caregiver burden was significantly heightened in the MCI Conv than the MCI Stable group as early as 36 months before conversion (t = 2.24, p = 0.026, FDR‐adjusted). We obtained similar caregiver burden robust effects differentiating the MCI Stable and CN groups for at least 36 months of stable condition (t=2.40, p=0.0256, FDR‐adjusted), though anosognosia index was able to differentiate the two groups for a shorter 12‐month period (t=2.80, p=0.005, FDR‐adjusted).

Conclusion

Anosognosia emerged as a differentiator as early as 4 years before conversion, while caregiver burden proved effective in distinguishing individuals at risk 3 years prior to the onset of conversion. These results underscore the significance of these measures in early detection and provide valuable insights for proactive interventions in the trajectory of Alzheimer's disease.
Meeting the demand: A pilot study to optimize service delivery for early Alzheimer’s disease using brief neuropsychological assessment
Authors: Naini Savana M. , Thompson Ryan C , Fuchs Kathleen , Rossetti M. Agustina , Manning Carol A , Reilly Shannon
Published: January 2025

Background

The increasing population of older adults and growing number of disease‐modifying therapies for Alzheimer’s disease (AD) highlight the need for timely differential diagnosis of neurodegenerative disorders despite high referral volumes. This study aimed to develop and pilot a brief neuropsychological battery to evaluate cognitive functioning in adults with suspected AD and improve service delivery by reducing the time between referral and diagnosis.

Methods

Patients were referred to the “early AD pathway” by their neurologist or geriatrician after an initial evaluation in an outpatient multidisciplinary dementia clinic. Eligible patients scored 18‐25/30 on a brief cognitive screening measure (Montreal Cognitive Assessment [MoCA]), had an amnestic clinical presentation, and were thought to have mild cognitive impairment (MCI) or mild dementia. The “early AD pathway” involved chart review, a brief clinical interview, and an abbreviated clinical test battery based on the NACC Uniform Data Set (UDS) Version 3 neuropsychological battery. Patients were provided feedback shortly after the assessment, and referring providers followed up with patients to discuss additional neurodiagnostic workup and/or possible treatments. Nine patients referred for the “early AD pathway” pilot were compared to general memory/cognitive referrals seen by the neuropsychology clinic during fall 2023 (n = 95). Retrospective data collection included demographic characteristics and relevant clinical information, including the time between referral and evaluation, MoCA total score, and post‐evaluation diagnosis. Non‐parametric analyses were used to compare the “early AD pathway” patients to those undergoing traditional clinic procedures.

Results

Preliminary results indicated significantly reduced wait times compared to traditional neuropsychological referrals (Mdiff
= 155.17 days, p<.001) and successful identification of individuals with MCI or mild dementia. Moreover, 8/9 participants had an amnestic cognitive profile, suggesting high sensitivity for identifying a likely neurodegenerative process (i.e., suspected AD) in this pathway. Importantly, this pilot sample was small and racially homogenous, indicating the need for broader recruitment going forward.

Conclusions

This pilot study demonstrated preliminary evidence for how to optimize neuropsychological service delivery to guide patients efficiently through an early AD identification process in a multidisciplinary clinic. This will be increasingly important as service demands and the number of pharmacological treatments increase over time.
Analyzing Sleep and Gait Dynamics through Digital Monitoring across Mild Cognitive Impairment (MCI) and non‐MCI Groups
Authors: Kim Minzae , Low Spencer , Sunderaraman Preeti , Au Rhoda , Shih Ludy
Published: January 2025

Background

Sleep apnea and insomnia are risk factors for dementia. Slower gait and increased gait variability are also associated with increased risk of MCI, linked to cognitive decline. Wearable digital sensors can serve as vital tools for measuring sleep and motor function. While poor quality of sleep has been correlated with decline in cognitive function, the relationship between sleep quality and gait parameters is less characterized. We hypothesized sleep apnea and lower sleep quality were associated with gait speed, gait variability, and functional mobility.

Method

Participants aged 50+ (n=55, female=31) used a finger‐worn sensor with embedded plethysmography [Sleepimage] for at least three consecutive nights over two weeks, quarterly for eight quarters. Five major sleep parameters were evaluated: Sleep Quality Index (SQI), sleep efficiency, Apnea Hypopnea Index (sAHI) at 3% oxygen desaturation threshold, sleep latency, and stable non‐REM sleep percentage. Gait assessments were completed on‐site with inertial sensors [APDM Opals] worn on the wrists, shanks, and waist. It included timed walks with and without cognitive tasks and a Timed Up and Go (TUG) test. Relevant parameters included comfortable gait velocity, dual‐task walking velocity, and lateral step variability. Pearson correlations were used to assess the relationship between sleep and gait parameters. Mean values were compared between participants with and without MCI (MCI=8, Non‐MCI=47) and between slow and fast walkers (above or below 1 meters/second, fast, n=29, slow, n=26) using independent t‐tests.

Result

Mean sAHI was significantly greater in slow (22.39) than fast walkers (14.57, t=2.309, p=0.026). sAHI demonstrated a significant negative correlation with gait velocity (r=‐0.288, p=0.047) and a positive correlation with time required to stand from sitting (r=0.367, p=0.01). Better SQI (r=‐0.316, p=0.029), longer sleep latency (r=0.296, p=0.041), and stable non‐REM sleep (r=‐0.316, p=0.029) was significantly associated with increased lateral step variability. Mean lateral step variability was higher in participants with MCI (16.89) than those without (0.68, t=2.485, p=0.036); mean TUG time was longer in participants with MCI (12.21 seconds) than those without (9.85, t=‐2.755, p=0.028).

Conclusion

This preliminary analysis suggests associations between sleep disturbances and gait parameters associated with risk of cognitive decline. Constraints of sample size and participant diversity are acknowledged, informing the ongoing enrollment of the cohort.