bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenome‐wide association study and integrative cross‐omics analyses of cerebral white matter hyperintensities implicate novel gene networks related to Alzheimer’s disease
Authors: Yang Yunju , Yang Qiong , Knol Maria J. , Mishra Aniket , Armstrong Nicola , Adams Hieab H.H. , Smith Jennifer A , Breteler Monique M.B. , Grabe Hans J. , Wardlaw Joanna M , Launer Lenore J. , Longstreth William T , Seshadri Sudha , Debette Stéphanie , Fornage Myriam
Published: December 2022

Background

Cerebral white matter hyperintensities (WMH) on magnetic resonance imaging are markers of cerebral small vessel disease (cSVD), a major risk factor for Alzheimer’s disease and related dementia (ADRD). Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation (DNAm) has received little attention.

Method

We investigated the association of blood DNAm at approximately 450,000 CpG sites with WMH burden in 9,732 middle to late age adults from 14 cohorts. Integrative cross‐omics analyses followed to elucidate the role of identified DNAm in cSVD.

Result

We identified 12 single‐CpG and 46 region‐based DNAm associations with WMH burden. Our top discovery single CpG, cg24202936 (P = 7.6×10−8), was associated with F2 expression in blood (P = 6.4×10−5), and colocalized with FOLH1 expression in brain (posterior probability = 0.75). Some single‐CpG loci (cg17417856 and cg06809326) with suggestive evidence (P<1×10−5) were also identified as differentially methylated regions (DMRs) in PRMT1 and in CCDC144NL‐AS1. Mendelian randomization analyses showed that cg06809326 is causally associated with WMH burden (OR [95% CI]: 1.39 [1.03‐1.87], P = 0.03) and that expression of CCDC144NL‐AS1 mediates this association. DMR analysis, joint epigenetic association analysis, and multi‐omics colocalization analysis consistently identified a role of DNAm near SH3PXD2A, a locus previously identified in genome‐wide association studies of WMH. Gene set enrichment analyses revealed functions of the WMH‐associated DNAm loci in the blood‐brain barrier (BBB) and in the immune response. Integrative cross‐omics analysis identified 19 key regulatory genes in two WMH‐associated networks related to extracellular matrix (ECM) organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated peroxisome proliferator‐activated receptor alpha (PPAR‐α) agonist as a target drug for WMH, which was also proposed as a promising target for ADRD.

Conclusion

Our epigenome‐wide association study and integrative cross‐omics analyses implicate novel genes influencing WMH burden, which converged on pathways related to the immune response and to a compromised BBB possibly due to disrupted cell‐cell and cell‐ECM interactions. The results also suggest that PPAR‐α may contribute to lowering risk for WMH possibly through protection against BBB disruption, which may potentially modify the ADRD risk.
Plasma Oligomeric Amyloid‐β partially mediates the effects of Diabetes Mellitus on Cognition in Mild Cognitive Impairment
Authors: Ng Kok Pin , Soo See Ann , Sandhu Gurveen Kaur , Zailan Fatin Zahra , Saffari Seyed Ehsan , Kandiah Nagaendran
Published: December 2022

Background

Oligomeric amyloid‐beta (OAβ) is postulated to be the major neurotoxic species that is implicated in the pathophysiology of Alzheimer’s disease (AD). Emerging evidence suggest that plasma OAβ levels are higher in AD compared to cognitively unimpaired individuals and correlate well with AD biomarkers. Diabetes Mellitus (DM) is consistently linked to cognitive dysfunction and epidemiological studies show that patients with DM have an increased risk of AD. While cerebral amyloid deposition is hypothesized to be the link between AD and DM, the association of OAβ and DM on cognition among mild cognitive impairment (MCI) remains unknown. Here, we aim to evaluate the effects of plasma OAβ levels and DM on cognition among MCI patients from a memory clinic in Singapore.

Method

In this retrospective cross‐sectional study, 54 MCI patients (mean age 68.31, 44.4% males) stratified by DM diagnosis, underwent cognitive assessment and plasma OAβ measurements using the Multimer Detection System‐Oligomeric Aβ (MDS‐OAβ) in National Neuroscience Institute Singapore between 2019 to 2021. Multiple linear regression models evaluated the main effects of OAβ and DM on cognition while mediation analysis evaluated the effect of DM on cognition mediated via OAβ. All analyses were controlled for age, sex, education.

Result

13 (24.1%) of the total MCI cohort had DM and OAβ levels were higher in DM patients (0.68 vs 0.53 ng/ml, p=0.023).OAβ levels were associated with lower MMSE scores (β= ‐4.08, p=0.004) while DM was associated with lower MMSE (β = ‐1.26, p=0.046) and MoCA (β = ‐1.83, p=0.025) scores. Plasma OAβ partially mediates the effect of DM on MoCA scores (Figure 1).

Conclusion

The effect of DM on poorer global cognition is partially mediated by higher plasma OAβ levels. While these results need to be replicated in a larger cohort, our findings suggest that optimizing DM control among MCI may reduce the burden of OAβ and improve cognition.
Neurofilament light as a marker of neuro‐axonal injury and potential biomarker of disease progression in normal pressure hydrocephalus
Authors: Taghdiri Foad , Vasilevskaya Anna , Anastassiadis Chloe , Multani Namita , Lang Anthony E , Fasano Alfonso , Tang‐Wai David F. , Tartaglia Carmela
Published: December 2022

Background

The etiology of normal pressure hydrocephalus (NPH) is unknown. Patients worsen but the cause of the progression is unclear. A prognostic biomarker in NPH is required for selecting the best candidates for shunt surgery. Neurofilament‐light chain (NfL) is a marker of neuro‐axonal injury and is elevated in neurodegenerative disease, traumatic brain injury, stroke and encephalitis. The aim of this study was: (1) To compare cerebrospinal fluid (CSF) NfL of NPH patients with healthy controls (HC), and other neurodegenerative diseases: Alzheimer’s disease (AD), and Frontotemporal lobar degeneration (FTLD); and (2) To evaluate CSF NfL levels as a potential biomarker of disease progression in NPH.

Method

108 patients with CSF analysis: (a) NPH group (39 patients): ventriculomegaly on MRI or CT, negative AD biomarkers, clinical symptoms of NPH, improvement in gait after removal of a large amount of CSF. 14 patients of the unshunted NPH group had a 1‐year follow‐up scan. EVANS index was calculated for these participants; (b) FTLD group (45 patients): 5 behavioural‐variant frontotemporal‐dementia, 19 corticobasal syndrome, 3 frontotemporal dementia with motor neuron disease, 13 progressive supranuclear palsy, 3 semantic‐variant primary progressive aphasia (PPA), and 2 non‐fluent PPA; (c) AD group (19 patients): CSF biomarkers and cognitive symptoms consistent with AD; and (d) HC group (5 participants): cognitively and functionally normal. Levels of NfL in CSF were measured using single molecule array (Simoa) technology. All statistical analyses were corrected for multiple comparisons and age.

Result

NfL levels in patients with NPH were significantly higher than HC (1504.7±520 vs 702.5±170pg/ml, p < 0.001), and lower than FTLD group (1504.7±520 vs 3071.7±2830pg/ml, p=0.005). There was a trend for lower NfL in NPH compared to AD, (1504.7±520 vs 2305.4±1179.7pg/ml, p=0.056). There was a significant correlation between baseline NfL levels and increase in EVANS index (r=0.784, p=0.002) in the 14 NPH patients with longitudinal brain imaging.

Conclusion

CSF NfL levels in NPH patients suggests there is neuro‐axonal injury but is lower than some other neurodegenerative diseases (i.e., FTLD and AD). NfL may be a biomarker for neuro‐axonal injury and disease progression in NPH.
Relationship between longitudinal changes in amyloid deposition and incident dementia in non‐demented individuals age 80+
Authors: Lopez Oscar L. , Villemagne Victor L , Cohen Ann D , Snitz Beth E , Aizenstein Howard J , Klunk William E , Mathis Chester , Chang YueFang , Kuller Lewis H
Published: December 2022

Background

Incident dementia increases with age and is associated with amyloid deposition. There is little knowledge about the progression of amyloid deposition in non‐demented individuals age 80+. The purpose of this study was to determine the relationship between changes in amyloid deposition over time and incident dementia in non‐demented individuals followed for a period of 11 years.

Methods

We examined a group of elderly participants (baseline age: 85.86 + 2.84) who had clinical evaluations from 2009 to 2020 and up to 5 measurements of Pittsburgh compound‐B (PiB)‐PET. 94 participants had two PiB‐PET scans, 76 three, 18 four, and 10 five. Mean age was 95 at 2020, at which time 49% of the participants with two or more scans developed dementia and 61% were deceased.

Results

There was a gradual increase in amyloid deposition in all participants whether they were considered amyloid positive or negative at baseline. Time to dementia in baseline amyloid negative participants was 7.09 + 2.90 years (range 2.92 – 11.22), and in amyloid positive participants 5.6 + 2.10 (range 2.27 – 9.67). Baseline amyloid deposition was a significant predictor of increase deposition over time. In a Cox model controlled for age, sex, education level, APOE‐4 allele, mortality, and baseline MMSE, change in amyloid deposition from 2009 to 2010‐11 was not significantly associated with incident dementia (HR 2.19 (0.41‐11.73). Baseline continuous measures of amyloid deposition, cortical thickness and white matter lesions (WMLs) were strong predictors of dementia. Approximately 70% of the participants who converted to dementia had either significant amyloid deposition (SUVR ≥1.67), cortical thickness, or WMLs positivity at baseline.

Conclusions

There was a substantial and steady amyloid deposition in this age group. There were very few (10%) participants who developed dementia without being amyloid positive. Individuals classified as amyloid negative at baseline became incident amyloid positive (SUVR > 1.67) prior to the dementia diagnosis, and most individuals who were amyloid positive at baseline developed dementia, especially when neurodegeneration was present.
Derivation of cut‐offs for plasma neurofilament light in clinical routine using healthy subjects aged between 5‐90
Authors: Simrén Joel , Gobom Johan , Andreasson Ulf , Suárez‐Calvet Marc , Depypere Herman , Nyberg Lars , Borroni Barbara , Zetterberg Henrik , Blennow Kaj
Published: December 2022

Background

Plasma neurofilament light (NfL) is a dynamic and robust cross‐disease biomarker of neuroaxonal injury. However, to enable clinical introduction of the assay, establishing cut‐offs is crucial. Here, we sought to derive reliable cut‐offs by quantifying NfL in plasma in healthy individuals.

Method

Participants from eight cohorts of neurologically healthy participants spanning the ages of 5‐90 years were recruited. NfL was measured using commercial Quanterix® kits (Simoa® NF‐light Kit) on Simoa HD‐X or HD‐1 analyzers (Quanterix, Billerica, MA, USA). Age‐partitioned cut‐offs were determined at the 95th percentile, which was estimated using a rank‐based method. In addition, we introduced an internal calibrator (IC) to normalize values in‐between runs and a quality control (QC) system to ensure longitudinal stability of the assay in clinical routine.

Result

In total, we included 1724 (ages 5‐<18 years, n=27; 18‐<51, n=569; 51‐<61=614; 61‐<70, n=366; >70 150) individuals. Plasma NfL concentrations increased significantly with increasing age (r2 = 0.53, P < 0.001). We established the following age‐partitioned upper cut‐offs: <7 pg/mL in the group between ages 5‐17, <10 pg/mL for 18‐50, <15 pg/mL between 51‐60, <20 pg/mL between 61‐70, and <35 pg/mL for individuals >70 years. High and low QCs maintained coefficient of variation (CV) below 10%. Other laboratories seeking to introduce plasma NfL into clinical routine may send samples to achieve traceability to the data presented here.

Conclusion

To conclude, we established reference limits for plasma NfL across the lifespan. This will aid the introduction of plasma NfL into clinical routine, simplifying disease monitoring and diagnostics.
Which Language is More Affected in Bilinguals with Alzheimer’s Disease? Diagnostic sensitivity of the Multilingual Naming Test
Authors: Gollan Tamar H. , Stasenko Alena , Salmon David P.
Published: December 2022

Background

The present study aimed to determine if Alzheimer’s disease (AD) affects bilinguals’ ability to name pictures in both languages equally, and to determine what testing procedures best distinguish bilingual patients from controls.

Method

Sixty Spanish‐English bilinguals, including 19 with dementia and 41 controls with equivalent age, education, and bilingual proficiency level, were tested on the full 68‐items of the Multilingual Naming Test (MINT; Gollan et al., 2012) first in their dominant language and then in the nondominant language. Four naming scores were derived for each participant: one for each language, one for either‐language that counted items as correct if produced only in one of the two languages, and one for both‐languages that only counted as correct items that bilinguals named in both languages. We also considered whether item difficulty modulates which naming score is most affected by AD by dividing the MINT test into difficulty tertiles (easy = items 1–20; medium = 21‐44; difficult = 45‐68).

Result

Bilinguals with AD named fewer pictures than controls, but this group effect varied with naming score and item difficulty. With difficult and medium items the difference between patients and controls was significant only in the dominant‐language, whereas with easy items the opposite was true (i.e., the group effect was significant only in the nondominant‐language), a significant interaction between participant group, language‐dominance, and item difficulty (F(1,58) = 5.449, partial‐eta‐squared = .086, p = .023). The either‐language scoring procedure increased naming scores especially in balanced bilinguals, and to an equal extent in patients and controls. Critically, ROC analyses revealed that dominant‐language and either‐language naming scores are superior for classifying bilinguals as patients versus controls, and significantly better than nondominant‐language and both‐languages naming scores.

Conclusion

For assessment purposes, testing primarily or exclusively in the dominant language is best for detecting bilingual naming impairments. However, AD likely affects the ability to access names in both languages, and simple descriptions of language decline as “similar in both languages” or as affecting one language more than the other may be misleading in terms of theoretical implications for how two languages are represented and processed in the bilingual brain.
Cerebrovascular reactivity deficits in older adults with elevated levels of plasma vascular injury markers
Authors: Kapoor Arunima , Jang Jung Yun , Yew Belinda , Dutt Shubir , Li Yanrong , Sible Isabel J , Gaubert Aimee , Ho Jean K , Blanken Anna E , Marshall Anisa J , Shao Xingfeng , Soto Maira , Bradford David R , Rodgers Kathleen E. , Wang Danny JJ , Nation Daniel A
Published: December 2022

Background

Cerebrovascular dysfunction occurs with advancing age and is known to contribute to cognitive decline and dementia. Cerebrovascular reactivity is a marker of cerebrovascular function and represents the ability of cerebral blood vessels to regulate cerebral blood flow (CBF) in response to vasodilatory or vasoconstrictive stimuli. Deficits in CVR may contribute to vascular injury and cognitive impairment, however the mechanisms underlying this pathophysiology remain unknown. To explore whether inflammation and endothelial dysfunction may be involved in CVR deficits, we examined whether plasma levels of vascular injury markers indicative of such processes are associated with CVR deficits in older adults.

Method

Twenty‐five independently living older adults (mean age = 69.9 years; SD = 8.5; age range 55‐87 years; 24.0% male) free of dementia or clinical stroke were recruited from the community and underwent venipuncture and brain MRI. Plasma was assayed for vascular injury markers (Serum amyloid A (SAA), C‐reactive protein (CRP), intercellular adhesion molecule 1 (ICAM‐1), vascular cell adhesion molecule 1 (VCAM‐1)). Visually guided breath control exercises during pseudo‐continuous arterial spin labeling MRI were utilized to determine global (whole brain) CVR to hypocapnia (0.1Hz paced breathing; vasoconstriction) and hypercapnia (15s breath holds, vasodilation). Pearson correlation and multiple linear regression examined the relationship between circulating vascular injury markers and CVR to hypocapnia and hypercapnia.

Result

A significant negative association was observed between circulating levels of SAA and global CVR to hypocapnia (r = ‐.526, p = .017) as well as VCAM‐1 and CVR to hypocapnia (r = ‐.593, p = 0.007). These associations remained significant even after accounting for age and sex in multiple regression analyses.

Conclusion

Both SAA and VCAM‐1 are vascular injury markers known to be involved in inflammation and were found to be elevated in older adults with lower global CVR to hypocapnia. Inflammation is associated with atherosclerosis and can lead to endothelial dysfunction, which may ultimately contribute to cognitive decline. Our findings suggest that these biological processes may be related to CVR deficits. Whether higher levels of vascular injury markers represent a protective mechanism or indicate pathological processes remains unknown.
Equity and Engagement for Neurologic Research Participation at the Goizueta Alzheimer’s Disease Research Center of Emory University
Authors: Parker Monica W , Lah James J. , Dorbin Cornelya D , Davis Crystal P , Dye Clinton , Manzanares Cecelia , Goldstein Felicia C , Hepburn Kenneth , Levey Allan I.
Published: December 2022

Background

African Americans (AA) are disproportionately affected by Alzheimer’s disease[i], consistently underserved by social and health care systems, and greatly underrepresented in Alzheimer’s research.

Objectives

To better engage the Metropolitan Atlanta population of African Americans, the Goizueta Alzheimer’s Disease Research Center (ADRC) at Emory University has a dedicated focus on the recruitment and retention of AA individuals into ADRC research and brain donation programs.

Method

The cohort examined for this paper were entered into the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set, a longitudinal registry of NIA‐NIH, between November 2015 and February 2020. Equity in research participation has improved by sustaining relationships in the African American community with an educational outreach that addresses health, healthcare access, and the importance of research participation for the elimination of healthcare disparities.

Results

This population of research volunteers at the Goizueta ADRC, irrespective of race, were similar in age, educational attainment, marital status, and overall health status. Before consenting to research, the following behaviors were observed in older adults:

African Americans (AA) are 10.6 times more likely to attend in‐person community events when compared to European Americans (EA).

African American (AA) women require more “touches” (phone calls and attendance at educational outreach events) than both Caucasian women AND men.

African American (AA) women are the most distinct group with the longest time from first contact to consent.

Conclusion

These findings can be used to create a more specific approach to engaging older African American adults in longitudinal neurologic or other health research.
Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from ‘phenocopy’ non‐progressors
Authors: Keem Michael H , Eratne Dhamidhu , Lewis Courtney , Kang Matthew , Walterfang Mark , Loi Samantha M , Kelso Wendy , Cadwallader Claire , Berkovic Samuel F , Li Qiao‐Xin , Masters Colin L. , Collins Steven , Santillo Alexander , Velakoulis Dennis ,   The MiND Study Group
Published: December 2022

Background

Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non‐neurodegenerative ‘non‐progressor’, ‘phenocopy’ mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay.

Method

Cerebrospinal fluid (CSF) NfL, amyloid beta 1‐42 (AB42), total and phosphorylated tau (T‐tau, P‐tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow up information, patients were categorised as Progressors. Non‐Progressors were subtyped in to Phenocopy Non‐Progressors (non‐neurological/neurodegenerative final diagnosis), and Static Non‐Progressors (static deficits, not fully explained by non‐neurological/neurodegenerative causes).

Result

Forty‐three patients were included: 20 Progressors, 23 Non‐Progressors (15 Phenocopy, 8 Static), 20 controls. NfL concentrations were lower in Non‐Progressors (Non‐Progressors Mean, M=554pg/mL, 95%CI:[461, 675], Phenocopy Non‐Progressors M=459pg/mL, 95%CI:[385, 539], Static Non‐Progressors M=730pg/mL, 95%CI:[516, 940]), compared to bvFTD Progressors (M=2397pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non‐Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Static Non‐Progressors tended to have higher T‐tau and P‐tau levels compared to Phenocopy Non‐Progressors.

Conclusion

This study demonstrated strong diagnostic utility of CSF NfL in distinguishing bvFTD from phenocopy non‐progressor variants, at baseline, with high accuracy, in a real‐world clinical setting. This has important clinical implications to improve outcomes for patients and clinicians facing this challenging clinical dilemma, as well as for healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non‐progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL.
Metformin and dementia risk: A systematic review with respect to time‐related biases
Authors: Dai Jiahui , Ports Kayleen Deanna , Corrada Maria M. , O'Connell Joan , Odegaard Andrew O , Jiang Luohua
Published: December 2022

Background

Numerous observational studies have found metformin use to be associated with a reduced risk of dementia among individuals with diabetes, while others have found an increased risk. However, time‐related biases may exist in observational studies and result in spurious associations. Unaddressed time‐related biases can contribute to the inconsistent results of previous studies exploring metformin and dementia. Immortal time bias often produces effect estimates that biased toward an apparent “protective” effect of the medication, whereas time‐lag and time‐window biases can lead to either a “detrimental” or “protective” effect. The purpose of this study is to conduct a systematic review examining time‐related biases in the literature on metformin and dementia.

Method

The electronic databases of PubMed, Web of Science, and ProQuest were searched for the terms “Metformin” AND (“dementia” OR “Alzheimer’s Disease (AD)” OR “cognitive impairment”). No date restrictions were applied; however, only English language articles and human research were eligible. PROSPERO accepted the registration of this systematic review on 04/08/2021 (ID#: CRD42021240034). Data were extracted between 04/09/2021 and 09/24/2021. The Good Research for Comparative Effectiveness (GRACE) was used to evaluate the methodological quality of reviewed studies.

Result

Seventeen studies were identified: thirteen cohort studies, two case‐control studies, and two nested case‐control studies. Eleven (64.7%) of the identified studies reported a reduced risk of dementia associated with metformin use; two articles (11.8%) suggested metformin increased dementia risk, while four articles (23.5%) concluded no significant association between metformin use and dementia risk. Of the seventeen reviewed studies, immortal time bias was not addressed in eleven studies (64.7%). Time‐lag bias was not addressed in ten articles (58.8%), and four articles did not address time‐window bias (23.5%) (Table 1). Two studies addressed most time‐related biases effectively and received relatively high GRACE scores (9 and 12, respectively). Both of them found no significant associations between metformin use and dementia.

Conclusion

None of these reviewed studies addressed all time‐related biases specifically, illustrating time‐related biases are still common in the observational studies investigating the impacts of anti‐diabetic medications on dementia risk. The studies addressed most biases concluded no associations between metformin use and dementia.
Hexahydrocurcumin protect myelin damage in Alzheimer’s disease ‐like pathology in bilateral common carotid artery occlusion
Authors: Jearjaroen Pranglada , Tocharus Chainarong , Tocharus Jiraporn , Apichart Suksamrarn
Published: December 2022

Background

Age‐related dementia is usually found in the condition of chronic cerebral hypoperfusion (CCH) by altering the regional cerebral blood flow (rCBF) that causes neuronal damage. The white matter and hippocampal areas are the regions sensitive to CBF lowering which can change that local metabolic stress, initiate inflammatory processes and thereby neuronal cell injury that become the cognitive impairment.

Method

Male rats underwent with the bilateral common carotid artery occlusion (BCCAO) for 28 days, were divided into 3 groups; (1) sham group: sham operated + 0.1% hydroxyl cellulose; (2) BCCAO group: BCCAO operated + 0.1% hydroxyl cellulose; (3) HHC group: BCCAO operated + HHC 40 mg/kg. All rats were evaluated memory impairment by the Morris water maze test, then the brain tissues were investigated the protein expression by Western blotting analysis (APOE, IL‐1β, TNFα, MBP, p‐Tau), determined Aβ40‐42 levels by ELISA kit, and myelin integrity via TEM.

Result

The BCCAO group significantly decreased time in the target quadrant as it represented cognitive impairment, increased pro‐inflammatory cytokines, loss of myelin basic protein and myelin integrity compared to the control group. Moreover, BCCAO upregulated Alzheimer’s disease (AD) markers including p‐Tau and the levels of Aβ40‐42. On the other hand, hexahydrocurcumin (HHC) treatment group significantly attenuated cognitive deficit, pro‐inflammatory cytokines released, and myelin integrity compared to BCCAO group. Furthermore, HHC also mitigated AD markers by decreasing p‐Tau and Aβ40‐42 levels.

Conclusion

The CCH induction by the model of bilateral common carotid artery occlusion (BCCAO) 28 days shows the cognitive impairment, inflammatory burst, and white matter injury. Moreover, BCCAO is able to accelerate AD markers. However, HHC treatment protects cognitive deficit and white matter injury drive AD by inhibiting inflammatory responses.
CSF immune activation in Alzheimer’s disease driven by tau‐ and not amyloid pathology
Authors: Nordengen Kaja , Kirsebom Bjørn‐Eivind , Richter Grit , Pålhaugen Lene , Selnes Per , Gisladottir Berglind , Waterloo Knut , Rongve Arvid , Aarsland Dag , Fladby Tormod
Published: December 2022

Background

Genetic studies suggest involvement of the immune system in Alzheimer’s disease (AD) development, and neuroinflammation has been suggested as a key driver of AD. We here employ cerebrospinal fluid (CSF) markers to study whether immune‐ and glial activation are primary features of early amyloid plaque deposition, or follow significant tau pathology as the disease progresses.

Method

We included n=267 non‐demented cases with repeated CSF samples (1‐6 years). The presence of amyloid pathology (A), tau‐tangle pathology (T) and neurodegeneration (N) using Aß42/40 ratio, p‐tau181 and total‐tau were determined at baseline and follow‐ups. We then selected participants (n=226) that remained stable A‐/T‐/N‐ (n=134), A+/T‐/N‐ (n=33) and A+/T+/N+ (n=34) over time and cases that progressed from A‐/T‐/N‐ to A+/T‐/N‐ (n=14) and A+/T‐/N‐ to A+/T or N+ (n=11). Other A/T/N categories (e.g. A‐/T or N+) were excluded. Mixed Linear Models (MLMs) were used to measure longitudinal changes in CSF sTREM2, YKL‐40, clusterin, fractalkine, MCP‐1, IFN‐γ, IL‐6, IL‐18 and IL‐10 between groups with stable A‐/T‐/N‐ group as the reference. All models included age, sex and number of APOEε4 alleles as covariates.

Result

Compared to stable A‐/T‐/N‐, cases progressing from A‐/T‐/N‐ to A+/T‐/N‐ had lower sTREM2 levels (p=.022) over time, and both fractalkine (p=.053), IFN‐γ (p=.055) and clusterin levels (p=.068) showed trend levels towards lower levels. In stable A+/T‐/N‐ cases, YKL‐40 (p=.007) and fractalkine (p=.043) were lower than stable A‐/T‐/N‐ over time. A+/T+/N+ cases had markedly higher sTREM2, fractalkine and clusterin levels (all p<.001) that remained high over time. In this group the YKL‐40 levels were also higher at baseline (p<.001) and increased slightly over time (p=.032). There were no between‐group differences at neither baseline or over time in the CSF levels of MCP‐1, IL‐6, IL‐18 and IL‐10.

Conclusion

Amyloid pathology alone was not associated with increased immune and glial activation in our cohort, and several of the CSF immune markers were lower in both those progressing to A+/T‐/N‐ and the stable A+/T‐/N‐. An increase in activation markers was only shown in cases with tau‐pathology at baseline, or in cases that developed tau pathology during the follow‐up period, suggesting immune activation in response to tau pathology.
Changing views of old age and dementia for children in elementary schools in The Netherlands
Authors: Bormans Kasper , Zwakhalen Sandra ,   The department of Health Services Research is part of the Care and Public Health Research Institute (CAPHRI) of the Faculty of Health, Medicine and Life Sciences
Published: December 2022

Background

Children have negative stereotypes about aging and dementia from a very young age. These mental images are harmful to their own well‐being in later life and toxic to their approaching behavior of elderly people. There is an urgent need for positive interventions that give children a more constructive image of old age and dementia.

Method

We organized an innovative 14‐week educational trajectory about positive aging for two school classes of Dutch pupils of 10 years old. The young participants (n = 40) received communicational training to interact in a meaningful way with grandparents and unfamiliar people with dementia. Before and after the intervention, the children made four drawings of elderly people (unfamiliar, healthy & happy, unhealthy & unhappy, grandparent). The evolution of the drawings will be analyzed with an emphasis on the appearance, the location, the activity and the social network of the elderly.

Result

[Data will be collected in March – June 2022] We predict that the positive interventions will be visible in the evolution of the children’s drawings. We hypothesize the post‐test drawings to depict more social interactions between generations and showing a wider range of activities that differ from unhealthy and sedentary lifestyles.

Conclusion

The negative perceptions about old age and dementia arise at a young age and are detrimental later in life. Positive interventions are able to alter these internalized representations by changing the perspective on old age and dementia in children.
Digitally enabled Cognitive Assessments in the Identification and Intervention for Dementia in Elderly Africans (IDEA) Study
Authors: Urasa Sarah , Boshe Judith , Paddick Stella‐Maria , Mushi Declare
Published: December 2022

Background

The Alzheimer’s Disease International (ADI) reports that the Sub‐Saharan African population age 65+ will double in less than 25 years. That compares to high income countries whose doubling of this same age group took between 45‐115 years. ADI estimates 7.2% dementia prevalence rate in those 60+ years old. Incidence rates have been estimated to be lower, 4.1/1000 person years for those ages 60‐64, which is lower than that of high income countries, but these data come from only 5 studies involving 6 cohorts; total n=9,494). The paucity of AD related research in Sub‐Saharian Africa is alarming given the aging demographics and requires an immediate and rapid response to drastically increase research efforts. The Tanzanian community‐based Identification and Intervention for Dementia in Elderly Africans (IDEA) Study is testing whether digitally enabled cognitive assessment methods will provide a framework from which to accelerate expanded AD related research in Sub‐Saharan African countries.

Methods

The IDEA study was initiatied in 2014. It has been longitudinally assessing participants (n=437), age 65 years and older through biennial examinations that includes dementia related risk factors including Sociodemographics, cognitive tests, medical history, blood pressure, and grip strength. To this protocol, and in collaboration with the Davos Alzheimer’s Collaborative Global Cohort Development program, will be added the collection of longitudinal AD‐related digital phenotypes through the use of a tablet in the clinic and through smartphone applications that can be self‐administered on a more frequent basis from the person’s place of residence.

Results

We will present demographic and clinical characterization of the cohort to date. We will further discuss both the challenges and the opportunities provided through the added digital phenotyping protocol. We will also examine how being part of the DAC international network of research will help accelerate expansion of research not just within Tanzania, but potentially to other Sub‐Saharan countries.

Conclusions

Digital assessments offer a feasible and cost effective method for expanding dementia research in lower income regions who are facing near term realities of an aging population, but are still lagging in research that can inform healthcare preparedness.
Association of plasma inflammatory and metabolic biomarkers with plasma ADRD biomarkers in community‐dwelling older adults
Authors: Parker Daniel C , Kraus William E. , Huffman Kim M. , Morey Miriam C. , Hall Katherine S. , Cohen Harvey Jay
Published: December 2022

Background

Alzheimer’s disease and related dementias (ADRD) are associated with changes in inflammatory and metabolic biomarkers. Here, we evaluated associations among inflammatory and metabolic biomarkers previously‐associated with age related‐morbidity and plasma p‐Tau181, Aβ‐42/Aβ‐40 ratio, neurofilament light (NfL), and glial fibrillary acid protein (GFAP) in community‐dwelling older adults.

Method

We evaluated cross‐sectional associations of a panel of inflammatory and metabolic biomarkers with plasma ADRD biomarkers – quantified using the Quanterix SIMOA platform – in a subset of older adults from the Duke Performance Across the Lifespan (PALS) study (N=317; Age=75±8.6; MoCA=25±3.4). Inflammatory and metabolic biomarkers included TNF‐α, TNFR‐I, TNFR‐II, d‐dimer, IL‐6, VCAM‐1, G‐CSF, RANTES, MMP3, paraoxonase activity, adiponectin, uric acid, 11 free amino acids, and 45 acylcarnitines. We applied principal components analysis (PCA) separately to the inflammatory biomarkers, amino acids, and acylcarnitines. We used multivariate multiple regression to associate biomarker PCs with ADRD biomarkers, adjusting for age and sex.

Result

Biomarkers were not normally‐distributed and were log‐transformed prior to PCA. We identified 3 inflammatory principal components (PCs), 5 acylcarnitine PCs, and 2 amino acid PCs. Of these, two inflammatory PCs, one acylcarnitine PC, and one amino acid PC were associated with plasma ADRD biomarkers (all Wilk’s Λ p<0.01). On univariate analyses, one inflammatory PC loading positively on G‐CSF and RANTES associated with lesser concentrations of p‐Tau181, NfL, and GFAP (all p<0.05). An amino acid biomarker PC loading positively on hydrophobic amino acids associated with lesser concentrations of NfL and GFAP (all p<0.001). An inflammatory PC loading positively on TNF‐α, TNFR‐I, TNFR‐II and IL‐6, and d‐dimer associated with greater concentrations of p‐Tau181 and NfL (all p<0.01). An acylcarnitine PC loading positively on short‐chain acylcarnitines was associated with greater concentrations of NfL (p<0.001). None of the biomarker PCs significantly associated with the Aβ‐42/Aβ‐40 ratio.

Conclusion

In community‐dwelling older adults, biomarker PCs loading on G‐CSF, RANTES, and hydrophobic amino acids were associated with lesser concentrations of some plasma ADRD biomarkers, while an inflammatory PC loading on TNF‐α, TNFR‐I, TNFR‐II, and VCAM‐1 was associated with greater concentrations. Our findings provide insight into the association of inflammatory and metabolic biomarkers with plasma biomarkers of ADRD pathology.
The effects of 12‐week mobile phone based cognitive intervention on brain function in patients with mild cognitive impairment
Authors: Kim Bori. R. , Jeong Jee Hyang , Kim Geon Ha
Published: December 2022

Background

Cognitive intervention (CI) has been known to improve cognition and to delay cognitive decline in patients with mild cognitive impairment (MCI). The purpose of this study was whether our newly developed, mobile‐phone based CI with a chat bot for 12 weeks changed brain function and cognitive performance in patients with MCI.

Methods

A single‐blind randomized controlled trial was conducted in 60 older adults with patients with amnestic MCI. Participants were randomized into the two groups: the mobile phone based CI with chat bot (CI) (n=30) group and waitlist control group without CI (Control) (n=30) groups. A total of 13 mobile‐phone based CI programs were developed targeting for attention, memory, visuospatial, calculation, language and frontal executive functions. The CI comprised 60‐min‐session per day for 12 weeks. The primary outcome was the changes in brain function measured by resting state electroencephalogram (EEG), which was measured in eyes open and eyes closed conditions for 3 minutes each, with a 19‐channel wireless EEG device. The secondary outcome was the changes of cognitive function measured using the Cambridge Neuropsychological Test Automated Battery.

Results

There were no baseline demographic and clinical differences between the CI and the control groups. EEG analysis after 12‐week showed increased beta wave on the frontal areas in the CI group, while decreased beta wave on the frontal areas in the control group. In addition, CI group also demonstrated improvement in attention domain compared to the control group.

Conclusion

Considering that increased beta wave is associated with attention performance, our results suggest that the 12 week mobile‐phone based CI with chat bot could help improve brain function in patient with MCI.
The Relationship of Perceived Health Literacy and Vaccination Hesitancy in People with Dementia Associated Disorders
Authors: Kaczmarek Olivia , Baek Steven , Peraza‐Bonilla Sophia , Teng Ellie , Sethi Avtej , Bumstead Barbara , Zarif Myassar , Gudesblatt Mark
Published: December 2022

Background

Dementia associated disorders (DAD) refers to clinical conditions that are typically characterized by progressive cognitive impairment (CI) that interferes with an individual’s ability to function independently. In routine care CI in DAD may be poorly recognized and can vary considerably in degree and combination across multiple cognitive domains. Therefore, clinical judgement may be insufficient alone to identify CI across these varied types/degrees, and how CI may directly affect both patient quality of life and decision‐making. Patient reported outcomes (PRO) are used to survey patient perception of their disease across varied real world impact. The BRIEF Health Literacy (HL) survey (BHL), Electronic health literacy (eHealth Literacy Scale, EHL) and the psychological antecedents of vaccinations (Vaccine 5C, V5C), vaccine hesitancy, have not been explored across these areas in people with DAD (PwDAD).

Method

Retrospective cross‐sectional analysis of PwDAD who completed the following PRO’s V5C, EHL, and BHL in routine care.

Results

146 PwDAD, average age of 72+/‐15 years. Linear regression statistics were used to analyze trends between individual V5C questions with the BHL and EHL. Significant correlations were found as follows (p<0.01): V5C‐2 (the need for vaccination)vs BHL (r = .2), V5C‐3 (everyday stress interfering with vaccination) vs BHL (r = .2), V5C‐4 (I personally weight risks/benefits of vaccination) vs BHL (r = .3), V5C‐2 vs EHL (r = .2), V5C‐3 vs EHL (r = .1), V5C‐4 vs EHL (r = .2).

Conclusion

Lower perception health literacy ability (BHL) and lower ability to use electronic sources to gain information regarding their health literacy (EHL)in PwDAD impact decision and feelings regarding vaccination (i.e. the necessity of vaccination, stress as a barrier to vaccination, and risk‐benefit analysis respectively). Further investigation beyond perceptions to quantitative measures of CI across multiple cognitive domains (degrees/combinations) between the V5C, BHL, and EHL would prove useful in exploring these relationships and defining a path to enhance education to reduce vaccine hesitancy.
Relationships between metabolic activity in the brain and circulating metabolites vary by sex
Authors: Vu Michael M , Zammit Matthew D , Bansal Shivani , Gross Thomas J , Cheema Amrita K , Christian Bradley T , Mapstone Mark
Published: December 2022

Background

Glucose hypometabolism in the brain measured by [F‐18] fluorodeoxyglucose (FDG) positron emission tomography has been observed in a number of neurological disorders. In both Down syndrome (DS) and non‐DS populations, it is associated with higher amyloid load and lower cognitive performance.

Method

We obtained plasma samples, FDG PET and [C‐11] Pittsburgh compound B (PiB) from a sample of 89 adults with DS (mean age [standard deviation] = 38.9[8.3] years). We measured levels of metabolites using targeted mass spectrometry. We calculated correlation constants between glucose uptake in discrete brain regions, global amyloid load, and plasma metabolite levels. We examined the effect of sex and age on these correlations.

Result

We found significant correlations between plasma metabolites, primarily lipids, and FDG PET signal in the brain with regional specificity. Additionally, metabolites which were positively associated with FDG PET signal in a specific brain region were negatively associated with amyloid load and vice versa. While FDG PET signal in each region were not significantly different between males and females, their correlation with metabolites did. When examining females only, we find primarily lipid correlates again. The lipid metabolites negatively associated with FDG PET signal were distinguished from those lipids positively correlated with FDG PET signal by lipid class and not fatty acid length. In males, a completely distinct set of associations between brain regions and metabolites were observed. The number of FDR significant correlations decrease dramatically, however the magnitudes of these correlation constants are higher than those observed in females and there is very little overlap between any of the brain regions correlated with each metabolite.

Conclusion

The levels of brain amyloid and regional brain glucose metabolism in adults with DS are both reflected in the concentration of certain metabolites measured in blood plasma. Surprisingly, each brain region has its own orthogonal metabolic correlate. Moreover, these relationships are distinct in males and females. It will be important to explore the basis for these differences and determine if they are present in the general population. Future metabolic analysis of neurological diseases could also benefit from separate analysis in males and females so as not to obscure these differences.
Cohort Profile: The Community‐based Cohort of Functional Decline in Subjective Cognitive Complaint elderly study of the Geroscience Center for Brain Health and Metabolisms (GERO)
Authors: Slachevsky Andrea , Peters Anne , Zitko Pedro , Lillo Patricia , Thumala Daniela , Demanet Michele , Villagra Roque , Cerda Mauricio , Ibáñez Agustin , Gonzalez Christian
Published: December 2022

Background

Dementia worldwide is one of the most important causes of disability in the elderly and the most rapidly growing cause of death in the last 20 years in Chile. Cognitive complaint is considered a predictor for cognitive and functional decline (FD), incident mild cognitive impairment, and incident dementia. The GERO cohort aims to determine multidimensional risks factors associated with the prognosis of elderly with cognitive complaint on DF.

Method

The GERO cohort is a prospective cohort study of community‐dwelling elderly with cognitive complaint, without dementia, aged 70 or older living in 4 municipalities in Santiago, Chile. Participants were identified by a household census and information on demographics, biomedical, psychosocial, neuropsychological, neuropsychiatric, and motor function were collected by means of questionnaires and evaluations. Neuroimaging, blood, and stool samples were also obtained. FD was measured by the Pfeffer (score range 0‐33), Technology Activities of Daily Living Questionnaire (T‐ADLQ, score range 0‐100), and Everyday Cognition (ECOG, score range 0‐36) questionnaires.

Result

A total of 17,759 households were successfully approached, identifying 2,533 eligible subjects, accepting to participate 299 (59 men; 240 women). The mean age was 76.8±5.1, 25% older than 79. The average years of schooling was 8.9± 4.8. None of participants showed underweight. The average score for the Mini‐mental State Exam (MMSE) was 27.1± 2.4, with 5.3% of the sample scoring less than 23. The mean values for Pfeffer, T‐ADLQ, and ECOG were 0.8±1.3, were 11.9± 10.3, and 0.4±0.4 respectively. In the multivariate analysis MMSE was inversely correlated with the ECOG score (regression coefficient: ‐0.03 [95%CI ‐0.07; ‐0.002]. Pfeffer also was associated, but its statistical significance was lost after the multivariate adjustment.

Conclusion

Few other studies addressed cognitive complaint and functionality in elderly recruited at home. Elderly in the GERO‐cohort with cognitive complaint, without dementia, show a good level of functioning at the first assessment. Cognitive function measured by the MMSE seems to be associated to a subtle decline in general functioning as everyday cognition. Future multidimensional and prospective analysis of this cohort could bring more information about this association.