bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Technology Use with Subjective Cognitive Decline among Older Adults
Authors: Kiselica Andrew M , Stojanovic Marta , Waters Abigail , Benge Jared
Published: December 2023

Background

Older adults with a family history of Alzheimer’s disease (AD) have elevated rates of subjective cognitive decline (SCD). SCD is distressing for older adults and is a risk factor for future objective cognitive impairment, AD pathology, and AD diagnosis. Hence, it is important to understand whether lifestyle factors can mitigate SCD. One potentially protective factor is the use of technology‐based behavioral strategies for completing daily tasks. For example, in the face of subjective memory difficulties, an older adult may move from relying on memory to remember to pay bills to utilizing an automatic bill pay system. The current study examined whether greater use of technology for daily task completion was associated with fewer self‐reported cognitive symptoms, especially in individuals with family history of AD.

Method

Individuals over the age of 50 (range: 50‐85) completed surveys about their digital and analog approaches for completing daily tasks, as well as measures of physical activity and SCD. Participants with and without family histories of AD were matched on age, education, and sex. Multiple linear regression was used to assess main effects of family history and technology‐based behavioral strategy use on SCD. In addition, we examined whether family history of AD moderated this association.

Result

There was no main effect of technology‐based behavioral strategies on SCD (p = 0.259). However, there was an interaction effect between technology use and family history of AD on SCD. Specifically, in individuals with a family history of AD, more reliance on technology‐based behavioral strategies was associated with less SCD (t = ‐2.45, p = 0.018), but this relationship was not significant in individuals without family history of AD (t = 0.66, p = 0.511). This interaction remained significant even when controlling for another important protective lifestyle factor for SCD, physical activity.

Conclusion

Our findings suggest that technology‐based behavioral strategies are associated with less SCD in individuals with a family history of AD, independent of other protective lifestyle factors. Future recommendations provided by healthcare providers in the community to address subjective cognitive decline in cognitively unimpaired older adults might include focusing on technological assistance.
Minor neuropsychological deficits in SCD: Association with AD biomarkers and cognitive decline
Authors: Stark Melina , Wolfsgruber Steffen , Kleineidam Luca , Peters Oliver , Priller Josef , Schneider Anja , Fliessbach Klaus , Wiltfang Jens , Jessen Frank , Düzel Emrah , Bürger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Heneka Michael T. , Wagner Michael
Published: December 2023

Background

The clinical relevance and longitudinal impact of minor neuropsychological deficits (MND) in cognitively normal memory clinic patients with subjective cognitive decline (SCD) is still unclear. To address this, we set out to investigate whether MND in SCD patients are related to Alzheimer´s disease (AD) pathology and future cognitive decline. In addition, we wanted to assess whether SCD patients have an increased risk of neuropathology and cognitive decline even in the absence of MND.

Method

We included 233 cognitively normal, healthy control participants (HC) without subjective cognitive concerns and 439 memory clinic SCD patients with available baseline CSF and/or longitudinal cognitive data from the observational DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study. Participants, who scored at least 0.5SD below the mean on a composite measure calculated from the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological assessment battery, were classified as having MND. We compared the resulting participant groups regarding their baseline CSF Aβ42/40, p‐tau181, t‐tau and Aβ42/p‐tau181 levels, longitudinal preclinical Alzheimer´s cognitive composite (PACC5) trajectories and risk of progression to incident mild cognitive impairment (MCI).

Result

Compared to SCD patients without MND (n = 384), SCD patients with MND (n = 55, 12.5% of SCD sample) showed significantly elevated CSF AD biomarker levels, accelerated PACC5 decline and a higher risk of progression to incident MCI. Baseline MND had a positive predictive value of 57.0% (95%CI: 38.5‐75.4) and a negative predictive value of 86.0% (95%CI: 81.9‐90.1) for the progression to incident MCI within 3 years. SCD patients without MND showed increased PACC5 decline and a higher risk of incident MCI compared to HC participants without MND (n = 215), but did not differ from HC participants in their CSF biomarker levels.

Conclusion

MND are a risk factor for AD pathology and cognitive decline in memory clinic patients with SCD. The assessment of MND could thus provide useful information for AD risk stratification and enrichment in SCD samples. Importantly, SCD patients still have an increased risk for cognitive decline in the absence of MND.
Genome‐wide Association Study Meta‐analysis of Neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration
Authors: Ahmad Shahzad , Imtiaz Mohammed Aslam , Mishra Aniket , Wang Ruiqi , Rivero Marisol Herrera‐ , Bis Joshua C , Fornage Myriam , Roshchupkin Gennady V. , Hofer Edith , Logue Mark W. , Longstreth W.T. , Xia Rui , Bouteloup Vincent , Mosley Thomas H. , Launer Lenore J J. , Khalil Michael , Kuhle Jens , Rissman Robert A , Chêne Geneviève , Dufouil Carole , Djoussé Luc , Lyons Michael J. , Mukamal Kenneth J , Stone William Seth , Franz Carol E , Schmidt Reinhold , Debette Stéphanie , Breteler Monique M.B. , Berger Klaus , Yang Qiong , Seshadri Sudha , Aziz N. Ahmad , Ghanbari Mohsen , Ikram M. Arfan
Published: December 2023

Background

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro‐axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels and its genetic correlation with neurological traits could therefore provide new insights into shared molecular mechanisms underlying neurodegenerative disorders.

Method

To identify the genetic variations underlying blood NfL levels, we conducted an ancestry‐specific meta‐analyses of genome‐wide association studies (GWAS) based on 18,532 participants from 11 cohorts of European and 1142 participants (3 cohorts) of African‐American ancestry. In the post‐GWAS analyses, we performed expression quantitative trait loci (eQTL) analysis, LD‐regression, and genetic risk score (GRS) association analysis with neurological traits.

Result

In the European ancestry GWAS meta‐analysis, we identified two genome‐wide significant (P< 5×10−8) loci at 16p12 (UMOD), and 17q24 (SLC39A11). In the African‐American ancestry GWAS meta‐analysis, we identified three novel loci at 1q43 (FMN2), 12q14, and 12q21. Genetic correlation based on the European ancestry meta‐analysis with neurological traits showed a strong genetic correlation of NfL with Alzheimer’s disease (AD) (rg = 0.32, P = 1.74×10−6), total‐tau (rg = 2.01, P = 1.03×10−6), amyloid‐beta (Aβ)‐40 (rg = 0.80, P = 6.92×10−6),and Aβ‐42 (rg = 1.03, P = 4.39×10−5). A higher genetic risk score based on NfL‐associated genetic variants was also related to increased plasma levels of total‐tau (P = 1.97×10−4), Aβ‐ 40 (P = 2.24×10−5), Aβ‐42 (P = 2.92×10−4) in the Rotterdam Study.

Conclusion

This large‐scale GWAS meta‐analysis revealed multiple novel genetic loci of NfL levels in blood in participants from European and African‐American ancestry. Significant genetic correlation of genes underlying NfL with AD, Aβ‐42, and total‐tau may indicate a common underlying pathway of neurodegeneration.
Proteome‐wide effects and causality of familial Parkinson’s disease
Authors: Yu Lai Mei‐ , Benitez Bruno A.
Published: December 2023

Background

The causal mediators of phenotype‐associated genetic variation in ∼75 genetic loci associated with Parkinson’s disease (PD) risk, including LRRK2 and GBA1 key loci, remain unresolved. We integrated the cerebrospinal fluid (CSF) proteome and genomic data to uncover causal associations in genetically‐defined PD.

Methods

CSF proteome from the Parkinson’s Progression Markers Initiative (PPMI) cohort (N = 1158) was quantified using the 5K SOMAscan assay. We integrated whole genome sequencing data of 683 samples to identify genetic variants associated with protein levels (protein quantitative trait loci; pQTLs). pQTLs within a region of ± 1Mb from the sentinel SNP as cis‐pQTLs, otherwise, as trans‐pQTLs. We sought pleiotropic locus associated with multiple proteins. We used the latest meta‐analysis from Nalls et al.[1] as an outcome to implement two‐sample Mendelian randomization using TwoSampleMR[2]. We identified colocalized proteins for PD using coloc[3,4,5]. We identified associated proteins with sporadic PD (sPD), and PD with mutations in LRRK2, and GBA1. The pathway analysis was performed using pathfindR[6]. We built elastic‐net logistic regression models to select protein combinations for sPD, LRRK2+ PD, and GBA1+ PD prediction using glmnet[7]. Plasma proteome data from the Penn Udall and Multi‐site PDBP were used as replication cohorts[8].

Results

We found 701 cis‐ and 420 trans‐pQTLs, and 23 causal proteins; eight of which colocalized with PD risk loci. We found 92 pleiotropic loci, including the APOE and LRRK2 loci. We found 59, 271, and 127 proteins associated with sPD, LRRK2+ PD, and GBA1+ PD, respectively. The predictive models with 33, 154, and 66 proteins for precisely classifying sPD vs. controls (AUC = 0.835; PR‐AUC = 0.898; F1‐score = 0.852), LRRK2+ PD vs. sPD (AUC = 0.95; PR‐AUC = 0.918; F1‐score = 0.828), and GBA1+ PD vs. sPD (AUC = 0.877; PR‐AUC = 0.776; F1‐score = 0.688), respectively. LRRK2+ and GBA1+ PD associated proteins were enriched for dopaminergic synapse, proteasome, and lysosome pathways, and sPD‐associated proteins were enriched for neurotrophin, endocytosis, and chemokine signaling. We found 25 PD‐associated proteins in the Upenn Udall Discovery cohort and replicated 11 proteins in the PDBP replication cohort.

Conclusions

Our systems biology approach discovered causal PD proteins which could be used as drug targets and offers a novel methodology to improve our understanding of PD pathogenesis and prediction.
Integration of cerebrospinal fluid proteomics and clinical scaled scores for subtyping sporadic Parkinson’s disease
Authors: Lai Mei‐Yu , Palanisamy Divya , Benitez Bruno A.
Published: December 2023

Background

Molecular pathways and networks associated with sporadic PD (sPD) subtypes are still unclear. We applied a systems biology approach to identifying proteomic signatures associated with sPD, cognitive and motor scaled scores, brain volumetric measurements, and cerebrospinal fluid (CSF) phosphorylated‐tau (p‐tau), total‐tau (t‐tau), alpha‐synuclein (a‐syn), and amyloid‐beta (a‐beta) levels.

Methods

We used CSF proteomic data of sPD from the Parkinson’s Progression Markers Initiative (PPMI) cohort (n = 377 sPD vs. 182 controls) and built an elastic‐net logistic regression model, adjusting for age, sex, and principal components, for sPD risk prediction using glmnet[1]. We performed correlation of baseline proteome with cognitive (MoCA) and motor assessments (UPDRS‐I, II, and III), neuroimaging data (Dopamine transporter scan; DaTscan of mean bilateral caudate, putamen, and striatum thickness (mm)), and CSF biomarkers. We implemented weighted gene co‐expression network analysis (WGCNA) to group co‐expression CSF proteins for sPD and to subtype sPD by CSF biomarkers using WGCNA[2] and ConsensusClusterPlus[3].

Results

We found a CSF proteomic signature (59 proteins) differentially expressed in sPD compared to controls linked to neurotrophin, endocytosis, and chemokine signaling. There are 82 and 68 proteins differentially expressed in UPDRS‐II and UPDRS‐III scores. Three, 13, and 11 proteins were associated with caudate, putamen, and striatum volumes. We found proteins correlated with p‐tau (n = 1394), t‐tau (n = 1577), a‐syn (n = 1427), and a‐beta (n = 847) levels. We implemented a predictive model with 33 proteins for sPD (AUC = 0.83) that outperformed the models with UPDRS‐I (AUC = 0.71), MoCA (AUC = 0.67), p‐tau (AUC = 0.56), t‐tau (AUC = 0.61), a‐syn (AUC = 0.54), and a‐beta (AUC = 0.57) but underperformed UPDRS‐III (AUC = 0.99) or putamen (AUC = 0.99). WGCNA indicates CSF biomarkers are highly correlated to six protein modules for subtyping sPD: each module was enriched for different pathways, ME1 (SNARE and MAPK signaling), ME9 (autophagy), ME7 (lysosome and MAPK), ME6 (immune response), ME10 (proteostasis and phagocytosis), and ME2 (longevity regulating and mTOR). Those modules defined two subtypes of sPD by p‐tau levels (9.93 pg/mL, AUC = 0.909). MoCA (p = 0.035), t‐tau (p = 3.2×10−60), a‐beta (p = 1.7×10−22), and a‐syn (p = 4.6×10−32) were significantly lower in the subtype with low levels of p‐tau.

Conclusions

Integrating molecular profiling and clinical scale scores improves the prediction of sPD risk and identifies sPD subtypes.
Integrated Memory Care: Primary Care for Persons Living with Dementia
Authors: Clevenger Carolyn K
Published: December 2023

The Integrated Memory Care (IMC) program is a nurse practitioner led, physician‐supported primary care model which serves individuals living with Alzheimer’s disease and related dementias (ADRD) and their care partners living in the community. Individualized care plans align with patients’ goals, and patients benefit from care coordination provided by an expert team that includes nurses, social workers, occupational therapists, and dementia care assistants, all working directly with primary care providers. The IMC adds a palliative care perspective as well, emphasizing aggressive symptom management and advance care planning, thereby providing holistic care for individuals living with ADRD.

Over 2000 patients and family care partners have received care at IMC since 2015. The average age of the patient population is 78.6 years; 65% of patients are female; 42% of patients are non‐white. The practice has developed and tested dementia‐specific workflows that can be implemented in a fee‐for‐service primary care environment. Successful completion of dementia quality measures, such as documentation of dementia type and stage, as well as assessment of cognitive, functional, and behavioral symptoms, is >90%. The ambulatory care sensitive admission rate of patients enrolled in the program is 0.5‐0.9%, well below published rates of 13% to 15%. In a case‐matched control group of patients, the IMC relative risk of hospitalization was one‐half those managed in usual primary care.

The IMC represents a novel model of care for individuals living with ADRD and their care partners, achieving superior patient outcomes and representing a financially sustainable model for this growing population. Its primary care systems and processes provide an integrated pathway to quality care, thereby facilitating the identification of patients in the primary care setting who are living with ADRD.
Predicted Brain Age Difference Scores at Age 56 Are Associated with Executive Function Changes Across 12 Years
Authors: Gustavson Daniel E. , Elman Jeremy A. , Reynolds Chandra A. , Eyler Lisa T. , Fennema‐Notestine Christine , Gillespie Nathan A. , Neale Michael C. , Panizzon Matthew S. , Lyons Michael J. , Franz Carol E , Kremen William S.
Published: December 2023

Background

Predicted brain age difference (PBAD) scores are novel metrics which compare chronological age to age predicted from neuroimaging data. PBADs are highly relevant to Alzheimer’s disease (AD) and cognitive aging. Individuals with AD have predicted brain ages about 10 years older than their chronological age (Franke et al. 2010). Less is known about PBADs in midlife, but recent work on the sample studied here has demonstrated that PBADs are highly heritable (59‐75%), highly stable between middle‐ and early‐old age, and moderated by modifiable lifestyle behaviors earlier in midlife (age 40). The current study examined how midlife PBAD (mean age 56) predicted executive functions concurrently and longitudinally into early old age (mean age 68).

Method

We examined 779 non‐demented men in the Vietnam Era Twin Study of Aging (VETSA) who completed cognitive and neuroimaging assessments at up to three assessments (M = 56, 62, and 68 years). PBADs were based on two methods (Liem et al., 2017, Cole et al. 2019) which include information about grey matter or both gray and white matter. Executive function was based on six tasks spanning inhibition, shifting and working memory. Analyses controlled for age, diabetes, hypertension, and APOE‐ε4 dosage.

Result

Latent growth models revealed that greater PBAD at age 56 (i.e., greater brain age than chronological age) was associated with worse executive functioning at baseline and greater decline in executive functioning over the following 12 years. The latter association was observed only for PBADs that included white matter (Cole et al., 2019) and persisted even when excluding N = 61 individuals with amnestic mild cognitive impairment (MCI). Subsequent analyses indicated that associations were not moderated by APOE allele status or cognitive reserve (general cognitive ability at mean age 20).

Conclusion

Our findings indicate that PBAD is associated with executive functioning in midlife and predicts executive function changes into early old age. They also suggest that PBADs capturing more information about brain health are better predictors of executive function decline across midlife into early‐old age. Finally, the persistence of these effects within cognitively normal subjects suggests PBADs are important predictors of cognitive decline before the onset of MCI/AD.
Chasing the cell type‐specific molecular networks involved in Alzheimer’s Disease
Authors: Lopes Katia de Paiva , Vialle Ricardo A , Green Gilad Sahar , Fujita Masashi , Wang Yanling , Gaiteri Chris , Menon Vilas , De Jager Philip L , Habib Naomi , Tasaki Shinya , Bennett David A. A
Published: December 2023

Background

Alzheimer’s disease (AD) is the primary cause of dementia, characterized by accumulation of neuritic plaques and neurofibrillary tangles, accompanied by neuronal loss and gliosis. Single‐cell profiling shows that AD involves a complex interplay of every major brain cell type. However, the molecular mechanisms responsible for cell‐type‐specific transcriptional changes remain to be defined.

Method

We used systems biology methods to analyze bulk RNASeq from DLPFC tissues of 1,210 participants and snRNASeq of 424 individuals from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). We identified modules of co‐regulated genes, assigned them to coherent cellular processes, and assessed which modules were associated with AD traits such as cognitive decline, tangle density, and β‐amyloid deposition.

Result

From the bulk RNASeq, we found 34 coexpressed modules with at least 30 genes. These modules were enriched for GO terms such as Lipid metabolism (M09), Apoptosis (M32), and Mitochondria (M24). Because variation in cell type proportions can drive coexpression patterns between genes, we verified that changes in cell proportion did not account for the module trait associations. Integrating the bulk modules with cell counts, we observed that 38% (13) of all modules had their variance significantly explained by specific cell‐type counts, including 41% (7) of the modules enriched for cell‐specific gene makers. Eight modules were associated with AD traits, where module M03 showed the strongest association with cognitive decline (P‐value = 2.56×10−19). This module was not enriched for a particular cell type, suggesting preservation across brain cells. Next, we constructed networks by each cell type and performed Bayesian inference to predict distinct directional relationships between AD traits and modules in each cell‐type network. The strongest associations with pathology were found in mic_M46 (tangles) enriched with genes related to negative regulation of T cell activation, and mic_M45 (β‐amyloid) enriched for transcription factors. By contrast, Oli_M14 (e.g. genes UMAD1, TPCN1, BCL2L1), enriched with bulk M03 genes, was the best module directly associated with cognitive decline after conditioning on all other correlated modules.

Conclusion

Our findings show that single‐cell co‐expression networks of the aging brain can highlight distinct molecular programs involved in cognition and pathology accumulation.
Default mode network sub‐systems connectivity in atypical Alzheimer’s disease
Authors: Sintini Irene , Corriveau‐Lecavalier Nick , Jones David T. , Radford Jonathan Graff , Singh Neha Atulkumar , Botha Hugo , Martin Peter R. , Machulda Mary M. , Schwarz Christopher G. , Gunter Jeffrey L. , Petersen Ronald C. , Jack Clifford R. , Lowe Val J. , Josephs Keith A , Whitwell Jennifer L
Published: December 2023

Background

Disruption of default mode network (DMN) connectivity is common in Alzheimer’s disease. We investigated cross‐sectional and one‐year longitudinal changes in DMN sub‐systems in atypical clinical presentations of AD, in relation to age and tau.

Method

Sixty‐four amyloid‐positive atypical AD (Aty‐AD) patients diagnosed with posterior cortical atrophy (n = 35) or logopenic progressive aphasia (n = 29) were recruited by the Neurodegenerative Research Group. Patients underwent structural and resting‐state functional MRI, and [18F]flortaucipir PET at baseline and one‐year follow‐up. 140 amyloid‐negative cognitively unimpaired (CU) individuals from the Mayo Clinic Study of Aging were included as controls. Global tau SUVR was calculated in a meta‐ROI including parietal, temporal, and occipital regions. DMN connectivity was calculated in native space for posterior (pDMN), ventral (vDMN), anterior ventral (avDMN) and anterior dorsal (adDMN) DMN sub‐systems using the dual regression method. A global measure of DMN connectivity, the Network Failure Quotient (NFQ), was calculated as (vDMN_to_pDMN+ adDMN_to_pDMN)/(pDMN+vDMN). Linear mixed‐effects models were computed for each DMN connectivity measure, including diagnosis (Aty‐AD, CU), age, time and their interaction, and a per‐person random effect. SPM paired t‐tests were run to compare baseline and follow‐up images in Aty‐AD and CU separately. Linear mixed‐effect models were run in the Aty‐AD cohort only to investigate the effect of global baseline tau SUVR on each DMN connectivity measure.

Result

Mixed‐effects models showed evidence of lower cross‐sectional pDMN and higher adDMN connectivity in Aty‐AD relative to CU, with no significant time effects (Fig. 1). While connectivity in all DMN sub‐systems declined with age in CU, connectivity was higher in older Aty‐AD patients relative to younger, particularly in vDMN and pDMN. A similar trend was observed for NFQ, which was significantly higher in Aty‐AD, with a negative age effect (Fig. 1). In Aty‐AD, voxel‐based analyses showed moderate evidence of decline in vDMN connectivity and increase in avDMN connectivity over time (Fig. 2). Greater baseline global tau SUVR was associated with lower vDMN connectivity, cross‐sectionally and longitudinally (Fig. 3).

Conclusion

DMN connectivity was altered in Aty‐AD, with strongest alterations in younger patients. The vDMN declined over time, suggesting a shift in DMN connectivity with disease progression that was likely related to tau pathology.
SORLA‐retromer complex formation rely on receptor dimerization within the endosome
Authors: Andersen Olav M.
Published: December 2023

Background

SORLA acts as an endosome recycling receptor together with the retromer complex to escort cargo through the endo‐lysosomal tubular network. SORLA is encoded by the SORL1 gene, which is the gene most frequently mutated in patients with Alzheimer’s disease, although it is still not clear which of the many variants are (the most) pathogenic. Here, we studied the biochemistry and cell biology of a SORL1 variant that is found in several European families.

Methods

We used transfected cells to study SORLA maturation and shedding of the soluble sSORLA by Western blotting. Expression of non‐mutated and mutated receptor at the cell surface was determined by flow cytometry, and the intracellular localization and overlap with markers of Endoplasmic reticulum and endosome compartments investigated by immunocytochemistry and confocal microscopy. The cellular distribution of receptor dimerization was visualized using bimolecular fluorescence complementation and proximity ligation assays, and quantified using the GFP‐trap method.

Results

We showed that non‐mutated SORLA forms a dimer in retromer‐coated endosome structures, while the pathogenic SORLA protein is unable to form dimers, although it traffics to the endosome. This lack of dimerization in the endosome correlates with strongly decreased receptor maturation, expression at the cell surface, and shedding of its luminal sSORLA domain.

Conclusion

SORLA dimer formation is required for its association with retromer, which is important for efficient receptor maturation and delivery to the cell surface. Decreased cell surface expression of mutated protein with impaired dimerization leads to less shedding, showing how maturation and sSORLA production can reliably inform on the pathogenicity of SORL1 genetic variants in Alzheimer’s disease.
Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities
Authors: Cha Woo‐Jin , Yi Dahyun , Ahn Hyejin , Byun Min Soo , Jung Joon Hyung , Kong Nayeong , Jung Gijung , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young ,   KBASE Research Group
Published: December 2023

Background

White matter injury had been mostly considered a result of chronic ischemia caused by cerebral small vessel disease. However, recent studies reported that white matter degeneration could also be an important pathophysiological feature in Alzheimer’s disease (AD). This study aimed to identify the relationship between AD biomarkers, particularly amyloid‐beta (Aβ) and tau deposition, with white matter hyperintensities (WMHs) representing cerebral white matter injury.

Method

A total 456 older adults aging from 55 to 90 years including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aβ deposition, [18F] AV‐1451 PET for measuring tau deposition, and MRI scans with fluid‐attenuated inversion recovery image for measuring WMH volume. For PET scans, standard uptake value ratio (SUVR) was used for the analyses; combined regions of hemispheric white matter, inferior cerebellum and pons were used as the reference region when obtaining SUVRs. The relationships between Aβ or tau deposition and WMH volume were examined using multiple regression analysis. In this analysis, baseline Aβ or tau were used as independent variables, and baseline as well as change of WMH volume over 2 years were used as dependent variables.

Result

Baseline Aβ deposition levels had significant positive association with longitudinal change of WMH volume over 2 years (β = 0.238, p = 0.009), but not with WMH volume at baseline. Baseline tau was not related with any of WMH volume at baseline and longitudinal change of WMH volume over 2 years. We also found significant interaction effect between baseline Aβ deposition level and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aβ deposition was associated with increase of WMH volume over 2 years in female (β = 0.427, p = 0.001), but not in male.

Conclusion

Our findings suggest that Aβ deposition, but not tau, accelerates cerebral white matter injury, particularly in female.
Multimodal MRI and tau PET findings from the Autosomal Dominant Alzheimer’s disease cohort caused by the A431E PSEN1 Jalisco mutation
Authors: Ortega Nancy E , Pa Judy , Chui Helena C , Shi Yonggang , Ringman John M
Published: December 2023

Background

The A431E mutation in PSEN1 is a cause of Autosomal Dominant Alzheimer’s disease (ADAD) that represents a founder effect, apparently arising from the state of Jalisco, Mexico, with over 100 superficially distinct families being affected. The median age of symptom onset is 41 years, with about 40% of cases having an atypical presentation of substantial spastic paraparesis. This study aimed to identify the neuroimaging features associated with the A431E PSEN1 Jalisco mutation to elucidate its pathophysiology and to inform future clinical studies.

Method

Thirty‐one participants with or known to be at‐risk for the A431E PSEN1 mutation were enrolled in a comprehensive genetic, clinical, and imaging protocol including MRI and flortaucipir PET scans. Diffusion MRI and flortaucipir PET studies were conducted on sub‐samples of the cohort along with appropriate control participants.

Result

Peak flortaucipir standard uptake value ratio (SUVR) among A431E mutation carriers was predominantly in the lateral parietal cortices relative to the medial temporal lobes with disproportionate signal in motor and sensory cortex relative to persons with late onset AD. Flortaucipir SUVR in 6 brain regions (i.e., medial orbitofrontal, caudal and rostral anterior cingulate, parahippocampal, precuneus, and lateral occipital) were associated with neuropsychiatric symptoms in persons with or at risk for the A431E PSEN1 mutation. Among 21 A431E PSEN1 mutation carriers with available diffusion MRI images, the Ashworth score of spastic paraparesis correlated with mean diffusivity in several brain regions, particularly left inferior parietal, superior parietal, and paracentral lobules (r’s>0.8, p’s< 0.001). In a subset of 10 clinically impaired A431E PSEN1 mutation carriers, mean diffusivity in white matter tracts underlying multiple cortical areas was higher relative to 8 impaired persons with late onset AD or ADAD mutations that do not cause spastic paraparesis.

Conclusion

The pattern of flortaucipir distribution was atypical with disproportionate involvement of sensorimotor areas and parietal cortex. Higher flortaucipir signal was associated with more neuropsychiatric symptoms. Microstructural changes in white matter were more pronounced in persons with the A431E PSEN1 mutation and likely underlie the associated spastic paraparesis. The distinct neuroimaging features and associated neuropsychiatric manifestations observed in this cohort highlight the importance of comprehensively characterizing heterogeneous AD subtypes.
Transfusion‐dependent thalassemia patients develop cognitive impairment with gut dysbiosis
Authors: Suparan Kanokphong , Trirattanapa Kornkanok , Sriwichaiin Sirawit , Kerdphoo Sasiwan , Tantiworawit Adisak , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2023

Background

Thalassemia is an auto‐recessive hemoglobinopathy affecting populations worldwide. Although life expectancy of thalassemia patients has been increasing due to therapeutic advancements, neurocognitive complications have been continuously reported among transfusion‐dependent thalassemia (TDT). Interestingly, the relationships among cognitive decline, systemic iron burden, and gut microbial alterations in TDT patients remain to be determined.

Method

Twenty‐eight participants, including 14 TDT patients and 14 heathy controls, were recruited to evaluate a cognitive function using the Mental State Examination T10 (MSET10) test. Serum ferritin was employed to reflect a severity of systemic iron burden. Stool was collected to determine a gut microbial profile using a next‐generation sequencing of bacterial 16s rRNA V3‐V4 regions.

Result

TDT patients had the cognitive impairment, higher systemic iron burden, and gut dysbiosis when compared with the controls. TDT patients also had lower MSET10 scores than the controls (Figure 1A). In addition, an increase in serum ferritin was observed in the TDT, indicating that there was the iron burden in the TDT (Figure 1B). Moreover, gut dysbiosis in TDT patients as indicated by higher bacterial diversity and different microbial compositions in comparison with the controls were observed (Figure 1C and 1D). The MSET10 scores were negatively correlated with the levels of serum ferritin and gut microbial diversity (Figure 1E and 1F). Interestingly, the levels of serum ferritin were positively correlated with the gut microbial diversity (Figure 1G).

Conclusion

These findings suggest that a systemic iron burden may involve in an alteration of gut microbiota, and the systemic iron burden together with the gut dysbiosis may concurrently deteriorate a cognitive function in TDT patients. Therefore, an iron reduction with a gut microbial manipulation, such as a combined usage of an iron chelator with a probiotic supplement, should provide benefits to prevent neurodegeneration as well as gut microbial disturbance in TDT patients.
Neuropsycho‐linguistic study of agraphia and aphasia in Moroccan Arabic in patients with Alzheimer’s disease
Authors: Taiebine Mohamed
Published: December 2023

Background

Agraphia and aphasia are common symptoms of neurodegenerative diseases such as Alzheimer’s disease (AD). While most studies were carried out in English, to our knowledge no study has been conducted in Arabic, to characterize these neuro‐psycholinguistic impairments in AD.

Method

Our sample included 14 patients (4 with mild and 10 with moderate AD). They met the clinical criteria for AD (McKhann, 2011). The average age is 68.2 years (SD 6; 57‐77). The average number of years of education is 13 years (SD 2.9; 6‐16). The average duration of the disease is 4.2 years (SD 1.97; 1‐8) . The neurolinguistic assessment was used with Mini‐Linguistic State Examination test (MLSE, Patel et al., 2020; Taiebine et al, 2021) for the screening of language disorders. Furthermore, an exhaustive neuropsychological assessment has been carried out (global cognitive functions, memory, attention, verbal fluency, executive, praxis, and visuo‐constructional functions). The writing samples were analyzed using the MMSE sentence writing and MLSE writing subtests.

Result

Statistical analysis showed that MLSE scores were influenced by disease severity and duration, whereas education level and age had no effect. As AD progresses, additional impairments become apparent in other cognitive domains. However, the marked syntactic deterioration in MLSE, compared to other linguistic domains, is an atypical pattern, whereas syntax is generally preserved in AD. (Taiebine et al, 2021). Neurolinguistic assessment showed impairment at the macro‐ and micro‐linguistic levels in terms of functional words, verbs, cohesion, and coherence. The analysis of paragraphias showed that the most frequent errors were literal omissions with missing diacritics (36%), followed by graphomotor errors (30%) and allographic errors (10%). The allographic errors are mainly graphemic simplifications that share visuospatial similarities with target letters.

Conclusion

This study offers a new perspective on the linguistic characterization of AD. Moreover, it confirms the hierarchical decline in language. The pattern of post‐graphemic disorders found in our patients was consistent with the impairment of peripheral writing buffers in Arabic: graphemic, graphomotor, and allographic.
The neuropsychological palliative programs based on professionally oriented tests and quality of life of patients with Alzheimer’s disease
Authors: Sushko Viacheslav Viktorovich , Sushko Viktor Vasilievich
Published: December 2023

As a rule, in progressive memory disorders, memory impairment occurs in a certain sequence. One of the last things a person forgets is the knowledge and skills he or she acquired during his or her professional activities.

We treated five women with Alzheimer’s disease aged 65‐70 years old. They received standard medication according to medical standards for the treatment of Alzheimer’s disease. They also received daily palliative care based on neuropsychological programs that included a variety of psychological tests and professionally oriented psychological tests. During history taking, patients were asked about their occupation. On special cards containing photos of objects connected with the patient’s profession, the patient found an object he or she could remember and name. This could be done once or every day before palliative neuropsychological programs. Then, during palliative sessions, a photo of this object was attached to all the numbers in this task, and the patient performed the action not just with numbers, but with the number of a particular object. For example, with the professionally oriented Schultz table, the patient, who had worked as a trolleybus driver all her life, found and showed not just numbers but the number of accumulators. As the patient recognized the photo of the battery and was able to name it correctly. And during the professional orientation of the Schultz table, we attached a picture of the battery to each digit. Also, at the end of the class, the patients answered the ten questions of the Patient Quality of Life Test.

During palliative neuropsychological programs if patients could not do the test task because it was difficult for them, the next day we offered the patient to do a professionally oriented task which, as a rule, the patient did. Subjective assessment of the patient’s quality of life was higher if the patient managed to do everything. There was also a desire to stay in the class longer.
Safety and efficacy of acute ischemic stroke intervention in patients with cognitive decline: case‐control retrospective study
Authors: Naftali Jonathan , Auriel Eitan , Prado Keshet , Tzur Gal , Barnea Rani , Findler Michael , Rephaely Guy , Perlov Alin , Glik Amir , Keret Ophir
Published: December 2023

Background

Individuals diagnosed with mild cognitive impairment and dementia (MCI/Dem) are excluded from research on intervention for acute ischemic stroke; This research gap places stroke physicians worldwide in dilemmas while treating patients with cognitive decline. One example is acute stroke of large brain arteries, typically manifesting as immediate onset of severe neurological disability. Endovascular treatment (EVT), aka catheter‐base clot removal, is considered the gold‐standard treatment and when applied within hours after onset, can mitigate or reverse deficits and dramatically improve outcomes. Our goal was to evaluate efficacy and safety of EVT for acute stroke in MCI/Dem.

Methods

This is a single site retrospective study from Rabin Medical Center,2019‐2021. Inclusion criteria was new onset acute large vessel stroke receiving EVT treatment, ages 18‐85 years. Pre‐stroke cognitive status was assessed using previous diagnosis, assessments in geriatric / occupational therapy clinics, nurse functional questionnaire and rehabilitation interview. Individuals were dichotomized to MCI/Dem (any severity) and unimpaired via consensus between two behavioural neurologists. The MCI/Dem group was matched to unimpaired individuals for sex, age, pre‐stroke functional independence, and stroke arterial territory, severity and time to EVT. The outcomes were retrospectively assessed 90 days after stroke and included mortality, intracranial haemorrhage, and pre to post stroke difference in the modified Rankin scale (mRS), commonly used instrument for stroke functional independence.

Results

We identified 306 individuals with acute large vessel stroke who underwent EVT, of which 32 with pre‐stroke MCI/Dem. After matching, we saw no differences between non impaired group to MCI/Dem group in functional outcome measured by mRS change, (56% vs.53%, p = 0.8), brain hemorrhage(22% vs. 9%, p = 0.68) and mortality (25% vs. 12%,p = 0.2).

Conclusion

To our knowledge this is the first study to report on EVT outcomes in individuals with MCI/Dem. Our results suggest interventions for acute large vessel stroke may have similar efficacy and safety profile in individuals with pre‐stroke MCI/Dementia and thus challenge previous recommendations to exclude them from therapy. Our data is retrospective and thus of inadequate design to suggest change to clinical guidelines. Further research on stroke interventions in MCI/Dem is urgently needed to guide day‐to‐day clinical decision making
A multi‐center pooled analysis of individual imaging data of 14,876 non‐demented participants to create normative data for total and regional white matter hyperintensity volumes to support dementia diagnosis.
Authors: de Kort Floor , Biesbroek J. Matthijs ,   Meta VCI Map consortium
Published: December 2023

Background

White matter hyperintensities (WMH) are a common manifestation of cerebral small vessel disease and a major cause of cognitive decline and dementia. Recent studies show that the cognitive impact of WMH depends on their location in strategic white matter regions. WMH are highly prevalent among asymptomatic individuals and increase with age. For dementia diagnosis, identifying patients with excessive total and regional (strategic) WMH therefore requires age‐ and sex specific norms, which are currently lacking. We aimed to obtain normative data for both total and regional WMH volumes in non‐demented community‐dwelling individuals.

Method

We harmonized individual person data from 15 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Cohorts were eligible for inclusion if participants were recruited from the population, underwent brain MRI (with availability of FLAIR and T1 sequences) and cognitive testing. Cohorts that recruited patients based on the presence of cognitive symptoms were not eligible for inclusion. Individuals fulfilling criteria for dementia were excluded. WMH were segmented and registered to the MNI‐152 template. WMH maps were used to calculate total WMH volume and regional WMH volumes in 20 pre‐specified white matter tracts. Normative data on WMH volumes were derived from observed values in 5‐years age bands and reported as cut‐off values for percentiles. All volumes are normalized WMH volumes (i.e. calculated on the MNI‐152 template).

Result

We analyzed 14,876 individuals with a mean age of 63.9 years (SD 11.9), 52% of whom were female. Median WMH volume was 2.0 mL (normalized, IQR 3.9) for the total sample. Median WMH volume increased with age, from 0.25 mL (<45 years) to 7.3 and 12.8 mL (>85 years) for men and women respectively. The table shows total WMH volume cut‐off values for percentiles, stratified for age and sex (cut‐off values for regional WMH volumes not shown due to abstract size constraints).

Conclusion

This study provides age‐ and sex‐specific normative data on total and regional WMH volumes. This enables an individualized approach to interpreting total and regional WMH burden to support diagnosis in clinical practice.
Predicting progression of Mild Cognitive Impairment patients through four distinctive groups obtained by a dimensionality reduction algorithm
Authors: Silva‐Spínola Anuschka , Leitão Maria João , Lima Marisa , Bernardes Catarina , Duro Diana , Regueira Patrícia , Tábuas‐Pereira Miguel , Durães João , Baldeiras Inês , Arrais Joel P , Santana Isabel
Published: December 2023

Background

The application of machine learning (ML) algorithms can help improve diagnosis and predict progression/conversion to Alzheimer’s disease (AD) at prodromal stages (Mild Cognitive Impairment – MCI)1. Due to the heterogeneity of the population at early stages and the large amount of data available, the use of unsupervised learning techniques can show distinctive patterns and help move towards personalized medicine2,3. In this work, we implemented a dimension reduction algorithm with the intent of characterizing MCI patients and develop a multistate model of progression to AD.

Method

We processed 57 variables including demographic, clinical, neuroimaging, fluid biomarkers, and genetic information from a mixed population of 1041 MCI patients (544 followed at the Dementia clinic of Centro Hospitalar Universitário de Coimbra (CHUC) and 497 obtained by ADNI). Data was normalized and scaled. Afterward, we applied a dimensionality reduction algorithm (UMAP) in Python. Missing data was handled accordingly. From those with longitudinal measures (n = 351), we generated transition probability estimates by Non‐Markov Multi‐State modelling, based on the change in the status of diagnosis through time by the MMSE z‐score at each visit.

Result

We obtained 4 clusters associated to: 1) increased cognitive reserve; 2) AD signature; 3) behavioral/mood alterations; and 4) mixed presentation with cardiovascular risk factors. We obtained theoretical progression rates (from faster to slower) in MCI individuals categorized in groups 2, 4, 1 and 3. After the onset of symptoms, initial decline within MCI is expected to occur in the 1st to 3rd year (in order: groups 2, 1, 4 and 3) with 60‐83% probability, and from MCI to AD from those more advanced as early as 5 (group 2) to 66 months for those in an initial phase with slower decline (group 3).

Conclusion

Our results show added value for the application of ML techniques in processing data with the intent to improve the characterization and follow‐up of MCI patients. We suggest that these four groups should be targeted and considered for monitoring patient care.

1. Silva‐Spínola A, et al. Biomedicines 2022; 2.Chun MY, et al. Front Aging Neurosc. 2022; 3.Tam A, et al. J Prev Alz Dis. 2022.
Effects of pre‐analytical sample handling on the performance of plasma phospho‐tau217
Authors: Bali Divya , Hansson Oskar , Janelidze Shorena
Published: December 2023

Background

Pre‐analytical variables can greatly influence biomarkers concentration. Till now, only two studies have examined the effects of pre‐analytical factors on plasma concentrations of phosphorylated tau (p‐tau)1,2. Hence, in this study we investigated how pre‐analytical factors affect the performance of one of the most promising plasma biomarkers of Alzheimer´s Disease, p‐tau217.

Method

We included 50 β‐amyloid positive (Aβ+) and 50 Aβ− participants from the Swedish BioFINDER‐1 cohort. Plasma samples were either thawed at room temperature (RT) or on ice, centrifuged or not centrifuged and freeze‐thawed once, twice or three times. Plasma and CSF p‐tau217 were measured using immunoassay developed by Lilly Research Laboratories. Aβ‐status was determined by CSF the Aβ42/Aβ40 ratio.

Result

In the whole cohort, we found significant correlations between plasma p‐tau217 and CSF Aβ42/Aβ40 and p‐tau217 for all tested conditions (Table 1). Correlations between plasma p‐tau217 and CSF p‐tau217 were also significant for all conditions in the Aβ+ group (Table 1). However, in this group, correlations with CSF Aβ42/Aβ40 were only significant in the centrifuged samples (thawed at RT, Rs = ‐0.394, p = 0.005; thawed on ice, Rs = ‐0.406; p = 0.003). In Aβ− participants, significant correlations between plasma p‐tau217 and CSF p‐tau217 were found again only in the centrifuged samples (thawed at RT, Rs = 0.394, p = 0.005; thawed on ice, Rs = 0.334; p = 0.018, Table 1), with no significant correlations between plasma p‐tau217 and CSF Aβ42/Aβ40 for any of the conditions. Even though the accuracy to identify individuals with abnormal CSF Aβ42/Aβ40 or CSF p‐tau217 status was high for all conditions, the AUCs of samples that were thawed at RT without centrifugation were numerically lower than AUCs of other conditions (CSF Aβ42/Aβ40: 0.845 vs 0.872‐0.884; CSF p‐tau217: 0.866 vs 0.908‐0.924, Table 2). Furthermore, no differences were found in plasma p‐tau217 concentration between the samples that were freeze‐thawed once, twice or three times.

Conclusion

We found that while centrifugation improved the performance of plasma p‐tau217, but thawing temperatures and upto three freeze‐thaw cycles did not have significant impact. These results might be of importance for future development of standard protocols for pre‐analytical blood sample handling.