bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractBackgroundOligomeric 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.MethodIn 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.Result13 (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).ConclusionThe 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

AbstractBackgroundThe 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.Method108 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.ResultNfL 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.ConclusionCSF 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

AbstractBackgroundIncident 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.MethodsWe 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.ResultsThere 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.ConclusionsThere 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

AbstractBackgroundPlasma 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.MethodParticipants 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.ResultIn 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.ConclusionTo 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

AbstractBackgroundThe 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.MethodSixty 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).ResultBilinguals 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.ConclusionFor 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

AbstractBackgroundCerebrovascular 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.MethodTwenty‐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.ResultA 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.ConclusionBoth 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

AbstractBackgroundAfrican 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.ObjectivesTo 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.MethodThe 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.ResultsThis 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.
ConclusionThese 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

AbstractBackgroundDistinguishing 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.MethodCerebrospinal 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).ResultForty‐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.ConclusionThis 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

AbstractBackgroundNumerous 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.MethodThe 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.ResultSeventeen 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.ConclusionNone 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

AbstractBackgroundAge‐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.MethodMale 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.ResultThe 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.ConclusionThe 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.