bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of the ACE‐R’s sub‐items that best differentiate healthy controls, amnestic MCI and non‐amnestic MCI
Authors: de Oliveira Maira Okada , Tres Eduardo sturzeneker , Cassimiro Luciana , Avolio Isabella B , Brucki Sonia Maria Dozzi 
Published: December 2021

AbstractBackgroundThe Addenbrooke's Cognitive Examination‐Revised (ACE‐R) is a brief yet reliable test battery that provides evaluation of six cognitive domains (orientation, attention, memory, verbal fluency, language and visuospatial ability) and widely used to measure cognition. It was developed and revised to provide a brief test sensitive to the early stages of dementia, and is also effective for differentiating the subtypes of dementia, such as Alzheimer’s disease, frontotemporal dementia, progressive supranuclear palsy, and other forms of dementia associated with parkinsonism. Our objective was to identify which sub‐items of ACE‐R could differentiate health controls, amMCI and non‐amMCI.MethodData originated from Brazilian Aging Memory Study (BRAMS).110 subjects: health controls (HC) (n=22; age 73.6±6y; schooling 14±4y; 77.2% female), amnestic MCI (amMCI) patients (n=64; age 73±6y; schooling 11±5y; 81.2% female) and non‐amnestic (non‐amnMCI) patients (n=24; age 70±7y; schooling 12±45y; 83.3% female) assessed by neurological exam and neuropsychological assessment. The Brazilian version of ACE‐R was applied as part of the cognitive assessment in all participants, but was not used to determine diagnosis.ResultThe following items differentiated between HC and amMCI: 3‐words recall (p=0.04), name/address recall (p=0.02), Verbal Fluency Letter P (p=0.01) and Verbal Fluency Animals (p<0.01); No differences were found between HC and non‐amMCI and non‐amMCI and amMCI.ConclusionIdentifying sub‐items that best differentiates groups could add more information to the clinician regarding the diagnosis and progression of the disease.
Resilience and perceived stress in cognitively normal older adults during the COVID‐19 pandemic
Authors: Kuppe Madeline K , Gagliardi Geoffroy , Gatchel Jennifer R , Munro Catherine E , Marshall Gad A , Sperling Reisa A. , Amariglio Rebecca E. , Vannini Patrizia 
Published: December 2021

AbstractBackgroundPsychological resilience, a construct representing a person’s ability to return to their baseline when difficulties occur, can play an important role in determining outcomes in the face of stressors. Resilience is a crucial component to consider during times of prolonged stress, such as experienced during the coronavirus disease (COVID‐19) pandemic, given that chronic stress has been associated with cognitive decline and dementia. Here, we investigated whether psychological resilience modified levels of perceived stress (assessed over 7 months), as well as examined the influence of demographic variables and Alzheimer’s disease biomarkers on this relationship.MethodIn May‐November 2020 of the COVID‐19 pandemic, 39 cognitively normal participants (mean age=78.38; 53.85% female) in the Harvard Aging Brain Study (HABS) completed questionnaires assessing stress (Perceived Stress Scale, PSS) and resilience (only at baseline; Connor‐Davidson Resilience Scale), higher scores on each measure indicating greater stress and increased resilience, respectively. We used previously collected data to better characterize the cohort, with the Preclinical Alzheimer Cognitive Composite (PACC;mean=0.46, SD=0.79) to assess cognition, and PET imaging data to assess Aß burden. A hierarchical regression model was used to assess whether resilience could predict baseline perceived stress. A separate linear mixed effect model (LME) was used to explore how resilience, time, and their interaction may affect stress. Both models also included age, sex, education, cognition, and Aß status (SUVR>1.324).ResultPerceived stress levels were generally low (mean=13.54, SD=8.65, range=0‐35), and did not significantly vary over the study period (p>0.5; mean number of timepoints=3.13). Both models demonstrated a main effect of resilience, such that higher resilience was associated with lower stress levels (p<0.001;Figure 1). Perceived stress was not influenced by demographic factors, cognition or Aß status. No significant interaction was found between resilience and time in predicting stress levels longitudinally.ConclusionOur findings confirm that resilience is critical for coping with stress during the COVID‐19 pandemic, suggesting that resilience could be an important target for potential interventions in the future. Efforts at increasing resilience could not only help support older adults navigating stressful situations, but may also mitigate negative effects of stress on neurocognitive and mental health.
Design of novel bifunctional chelators for diagnostic 64Cu PET imaging in Alzheimer’s disease
Authors: Mirica Liviu M 
Published: December 2021

AbstractBackgroundMetal radiotracers exhibit beneficial properties that can improve in vivo positron emission tomography (PET) imaging over traditional radionuclides, such as longer half‐lives, facile last‐stage radiolabeling steps, and the potential for dual imaging‐therapy applications. Among such radionuclides, 64Cu exhibits a longer half‐life (t1/2 = 12.7 h) that allows for later PET imaging times and the ability to distribute 64Cu imaging agents to facilities that do not have an on‐site cyclotron.MethodThe employed approach uses a bifunctional chelator with two Aβ‐interacting fragments that dramatically improves the Aβ‐binding affinity and lipophilicity for favorable blood‐brain barrier (BBB) penetration, while the use of optimized‐length spacers between the Cu‐chelating group and the Aβ‐interacting fragments further improves the in vivo Aβ‐binding specificity and brain uptake of the corresponding 64Cu PET imaging agent.ResultHerein, we report to the best of our knowledge the first 64Cu PET imaging agent that shows appreciable in vivo brain uptake and exhibits high specific affinity for beta‐amyloid aggregates, leading to the successful PET imaging of amyloid plaques in the brains of 5xFAD mice versus those of WT mice.Conclusion64Cu PET imaging agents can be used for in vivo imaging of beta‐amyloid aggregates.
Contribution of amyloid and tau to cerebrospinal fluid fatty acid indices in preclinical and prodromal Alzheimer’s participants
Authors: Fonteh Alfred N. , Arakaki Xianghong , Cipolla Matthew , Chui Helena C. , Harrington Michael G. 
Published: December 2021

AbstractBackgroundSince Aβ42 derives from membrane‐bound amyloid precursor protein (APP), we propose that membrane lipid composition may influence how APP is processed. Therefore, we aim to determine if fluctuations in fatty acid metabolism accompany amyloid and tau pathology.MethodUsing neuropsychology and ELISA‐based Aβ42/T‐tau measures in CSF, we classify five groups of elderly subjects:
c
ognitively
h
ealthy with
n
ormal
Aβ

42/T‐
t
au (CH‐NAT, n=36 ), cognitively healthy with pathological Aβ42/T‐tau (CH‐PAT, n=34), and MCI participants with normal or pathological Aβ42/T‐tau (MCI‐NAT, n= 26; MCI‐PAT, n=12), and Alzheimer’s (n=25). We determined the unesterified fatty acid (UFA) levels and the fatty acid composition of CSF nanoparticulate (NP) fraction and supernatant fluid (SF) using GC/MS. We calculated the chain length, unsaturation, and peroxidation indices and the ratio of monounsaturated fatty acid (C18:1, oleic acid) to saturated fatty acid (C18:0, stearic acid) designated the stearoyl‐CoA desaturase (SCD) index.ResultUnesterified chain length, unsaturation, peroxidation, and desaturase indices are higher MCI‐NAT/PAT than in AD. In the SF fraction, fatty acid indices are higher in the prodromal MCI‐PAT state than AD. To determine if SCD could account for differences in unsaturation, we quantified the primary SCD substrate (C18:0) and product (C18:1) in CSF fractions. We found that unesterified C18:0 was lower while C18:1 was higher in MCI‐NAT than the other clinical groups. These changes in C18:0 and C18:1 levels resulted in a higher desaturase index in MCI‐NAT (0.35± 0.15) than in CH‐PAT (0.26±0.16, adjusted p‐value (q) = 0.0230) and AD (0.16±0.11, q < 0.0001). In the SF fraction, C18:0 levels are lower in MCI‐PAT than AD concomitant with a higher C18:1 in MCI‐PAT than AD. These fatty acid differences result in a significantly higher desaturase index in the prodromal MCI‐PAT (0.46±0.15) than in AD (0.28±0.11, q = 0.0067).ConclusionThese studies show an increase in the unsaturation and peroxidation indices in early AD that may result from enhanced brain desaturase activity. These data suggest that fatty acid indices are potential biomarkers of preclinical or prodromal AD. The increase in fatty acid indices followed by a decrease in dementia indicate a need for state or stage‐specific combinatorial preventive therapies.
Do fine motor impairments constitute a key feature of mild cognitive impairment? A systematic review and meta‐analysis
Authors: Lodha Neha , McCarthy Sarah 
Published: December 2021

AbstractBackgroundTypical symptoms of mild cognitive impairment (MCI) include impairments in memory, executive function, and visuospatial skills. While impairments in these cognitive domains are highly apparent after MCI, impairments in motor domain are not so conspicuous. Converging evidence suggests that individuals with MCI demonstrate motor impairments in lower extremity such as reduced balance and impaired gait performance. However, the impact of MCI on upper extremity motor impairments is not well understood. In the current meta‐analysis, we examine whether fine motor impairments are a key feature of mild cognitive impairment.MethodWe performed a systematic search of electronic databases for articles published between 1990 and 2019. The meta‐analysis included studies that compared healthy older adults and adults with a clinical diagnosis of MCI on fine motor tasks such as handwriting, finger tapping, and hand dexterity.ResultTen studies with over 800 participants qualified for inclusion. Rigorous meta‐analytic techniques using random effects model, forest and funnels plots revealed a standardized mean difference effect of 0.48 (95% CI = 0.77 to 0.19, p=0.001). This moderate effect indicated deficits in fine motor control are a likely feature of MCI.ConclusionThe cumulative evidence suggests that fine motor impairments are pervasive in MCI across a range of upper extremity motor tasks. Quantitative assessment of the decline in fine motor function in MCI may be promising approach to understand the changes in motor function that occur with the onset of Alzheimer’s disease and are clearly differentiated from normal aging‐related decline.
Digital speech‐based measures separate those with cognitive impairment from those without
Authors: Stegmann Gabriela M , Hahn Shira , Liss Julie , Berisha Visar , Mueller Kimberly D 
Published: December 2021

AbstractBackgroundMeasures of language have demonstrated value in the detection of cognitive decline. Here we automatically extracted speech (audio) and language (transcripts) features from Cookie Theft picture descriptions (BDAE) to develop two classification models separating healthy participants from those with mild cognitive impairment (MCI) and dementia.MethodWe used Dementia Bank and Wisconsin Registry for Alzheimer’s Prevention (WRAP) datasets and evaluated the first observation of Cookie Theft descriptions from 1011 healthy participants: 51 with MCI (based on MMSE scores) and 193 with dementia. From the samples, we automatically extracted metrics to fit two classification models, which: (1) separated healthy from MCI participants; and (2) separated healthy from dementia participants. To avoid overfitting and spurious patterns in the data, we used k‐fold cross‐validation, restricted the feature space to only clinically meaningful metrics, and used simple logistic regression models with no more than 5 predictors.ResultThe MCI classifier separated healthy and MCI groups (ROC AUC = .80; Figure 1). Predictors were: MATTR (proportion of unique words on 10‐word moving average; b = ‐16.0, z = ‐4.7, p‐val < .05); the ratio of pronouns to nouns (b = 28.1, p‐value < .05), and propositional density (b = ‐15.0, p‐value < .05). The dementia classifier separated healthy and dementia groups (ROC AUC = .89; Figure 2). The predictors were: parse tree height (sentence complexity; b = ‐1.3, p‐value < .05), mean length of word (surface form; b = ‐3.9, p‐val < .05), the proportion of relevant details correctly identified in a picture description (b = 10.7; p < .05), type‐to‐token ratio (proportion of unique words; b = ‐11.0; p‐value < .05), and the duration of pauses relative to the total speaking duration (b = 1.1, p‐value = .22).ConclusionBoth classifiers separated groups with ROC AUC >= 0.80, with the dementia classifier performing better than MCI classifier. Features in the models were clinically meaningful and interpretable, and relate to vocabulary (MATTR, propositional density, TTR, mean word length), syntax (parse tree height), language processing (pause duration/speaking duration), and ability to convey relevant picture details.
Progression of neuropsychiatric symptoms in pre‐dementia GRN and C9orf72 mutation carriers
Authors: Chatterjee Atri , Lee Hyunwoo , Mackenzie Ian R , Wittenberg Dana , Rademakers Rosa , Hsiung Ging‐Yuek Robin 
Published: December 2021

AbstractBackgroundNeuropsychiatric symptoms (NPS) are common in frontotemporal dementia (FTD) patients and may precede the clinical diagnosis of dementia. We hypothesized that GRN and C9orf72 mutation carriers have increased baseline burden and rates of progression of NPS compared to non‐carriers prior to the onset of dementia. To investigate, we examined a longitudinal cohort of FTD mutation carriers and non‐carrier family members.MethodWe analyzed data from 80 participants (21 C9orf72+ mutation carriers, 10 GRN+ mutation carriers, and 49 non‐carrier family members (NCs); mean±SD age in years: 47±13, 51±9, and 54±13 respectively) recruited through the University of British Columbia FTD Study. NPS were assessed annually with Neuropsychiatric Inventory (NPI), Frontal Behavioural Inventory (FBI) and Iowa Scale of Personality Change (ISPC) with a mean follow‐up of 5.8 years. For ISPC, we used both the “Change” (“Now” minus “Before”) and the “Now” measures. If a participant developed FTD during the follow‐up (N=2), we only analyzed observations collected before the conversion. We initially compared the baseline burden of NPI, FBI and ISPC adjusted for age and sex, among C9orf72+ carriers, GRN+ carriers and NCs. We then used random‐intercept mixed models to compare the rates of progression of NPS among genetic groups using total NPI, FBI, ISPC change and ISPC now scores as outcome measures and genetic status, sex, respective baseline scores, expected years to onset (EYO) and genetic group*EYO interaction term as dependent variables.ResultThere were no significant group differences in baseline demographic features or neuropsychiatric measures. In longitudinal assessments, NCs demonstrated minimal change in NPS measures. GRN+ carriers had significantly higher progression rates of NPI (p<0.0001) and ISPC “Now” (p=0.0004) compared to NCs. However, there were no significant differences in the NPS progression rates between C9orf72+ carriers and NCs.ConclusionAlthough there was no baseline difference in the burden of NPS among the genetic groups, GRN+ carriers had a faster progression of NPS compared to NCs prior to the onset of dementia. Future work is warranted to investigate the potential association between the NPS trajectories and structural/functional brain changes in FTD mutation carriers.
Plasma antioxidants and phospholipids and brain imaging biomarkers among non‐demented older adults
Authors: Koch Manja , Cronjé Héléne Toinét , Furtado Jeremy D , DeKosky Steven T , Fitzpatrick Annette L , Lopez Oscar L , Kuller Lewis H , Mukamal Ken J , Jensen Majken K 
Published: December 2021

AbstractBackgroundPrevious studies have linked dietary fatty acids and antioxidants to dementia risk and cognitive decline. The relationships of objective markers of fatty acid and antioxidant intakes with brain imaging biomarkers remain uncertain.MethodWe assessed the associations of antioxidants and phospholipids in plasma, collected in 2000‐2002, with brain amyloid‐ß deposition on PET scans and hippocampal and white matter lesion volume on MRIs in 2009 among 193 participants of the Ginkgo Evaluation of Memory Study who were free of clinical dementia. We used multivariable‐adjusted and inverse‐probability‐weighted robust linear regression models. We measured antioxidants by organic phase extraction followed by chromatographic analysis and individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by gas chromatography with flame ionization detection.ResultA total of 20 participants (10%) had mild cognitive impairment at baseline and 134 participants (69%) used either multivitamin, vitamin A or β‐carotene, or vitamin E supplements (Table 1). Higher plasma retinol,α‐tocopherol, and total vitamin E were related to higher future amyloid‐ß deposition (Table 2). Higher α‐tocopherol and total vitamin E were also related to less white matter lesion volume. Carotenoids were not significantly related to any of the brain imaging biomarkers.Higher concentrations of the saturated fatty acid margaric acid (17:0) were associated with more amyloid‐ß deposition (adjusted difference per 1 SD higher margaric acid: 0.10 standardized uptake value ratio; 95% CI: 0.02, 0.19) and smaller hippocampal volume (Table 3). In contrast, higher concentrations of the saturated fatty acid behenic acid (22:0) were associated with less white matter lesion volume. Higher oleic acid (18:1n‐9c, a major monounsaturated fatty acid), was related to more hippocampal volume. Higher concentrations of the n‐3 polyunsaturated fatty acid docosahexaenoic acid (22:6n‐3c) were associated with more amyloid‐ß deposition, while higher concentrations of linoleic acid (18:2n‐6cc; a major n‐6 polyunsaturated fatty acid) were associated with less amyloid‐ß deposition (adjusted difference per 1 SD higher linoleic acid: ‐0.10 standardized uptake value ratio; 95% CI:‐0.19, ‐0.01).ConclusionSpecific antioxidants and phospholipids may be associated with brain imaging biomarkers, a hypothesis that requires formal testing in long‐term intervention studies and that represents a possible preventive intervention,
Gamma sensory stimulation in AD patients, a randomized controlled trial
Authors: Boasso Alyssa , Hempel Evan , Hajos Mihaly , Malchano Zach 
Published: December 2021

AbstractBackgroundPreclinical studies in transgenic mice demonstrated that sub‐chronic 40 Hz gamma sensory stimulation effectively halted or reversed AD‐related pathology, increased synaptic density, improved cognitive function, and normalized circadian rhythm. The OVERTURE clinical trial (NCT03556280), funded by Cognito Therapeutics Inc., is a 2‐to‐1 randomized placebo‐controlled trial conducted to determine the safety, tolerability, and impact of gamma sensory stimulation on Alzheimer’s disease symptoms and biomarkers in humans.MethodThis US‐based 4‐site feasibility trial evaluated safety, tolerability, cognitive and functional symptoms, and biomarkers of target engagement, neurodegeneration, and AD pathology. The trial was conducted between June 2018 and July 2020. Participants age 50 and older with a diagnosis of mild‐to‐moderate Alzheimer’s disease (MMSE 14‐26) were randomly assigned (2‐to‐1: active‐control) to receive 6 months of 1‐hour daily 40 Hz audio‐visual or sham stimulation. Therapy was self‐administered at home with the help of a care partner, and patients, care partners, and assessment raters were blinded to group assignment.ResultA total of 135 subjects were screened, of whom 74 (55%) were randomized and 53 completed (72%). Safety was evaluated by MRI, a suicidality scale, and physical and neurological exams at baseline, 12‐, and 24‐weeks, and monthly assessments of adverse events. Tolerability was measured by device use data, daily diary, and user experience interviews. Symptomatic changes were assessed daily via a diary, monthly via ADL, QOL, and care partner burden scales, and quarterly via the ADAS‐Cog14, NPI, CDR, and Clock Drawing Test, and the MMSE at baseline and week 24. Biomarkers, including Amyloid PET, Plasma amyloid‐β1‐42, ptau217, GFAP, and Neurofilament light, EEG, and volumetric MRI were examined at 3‐month increments. APOE status was characterized at baseline. Actigraphy devices were worn continuously throughout the trial to assess daytime and nighttime activity.ConclusionThis feasibility trial is designed to demonstrate gamma sensory stimulation’s safety and tolerability, feasibility of daily in‐home use for AD patients, possible functional and symptomatic benefits, and both standard and novel biomarkers of AD pathology and neurodegenerative decline. Data will help inform the design of a larger study, including the development of patient selection algorithms, novel outcome measures and evidence of clinical efficacy.
Cognition and elevated blood pressure in community‐dwelling older adults with subjective cognitive decline: A cross‐sectional exploratory study
Authors: Silva Narlon Cassio Boa Sorte , Gill Dawn P , Owen Adrian M , Petrella Robert J 
Published: December 2021

AbstractBackgroundThe impact of blood pressure (BP) on cognition in older adults remains equivocal. We investigated the relationships between cognition (global and domain‐specific) and ambulatory blood pressure in older adults with subjective cognitive decline (SCD).MethodWe conducted a cross‐sectional exploratory analysis of data collected from 230 community‐dwelling older adults (age mean [SD]: 69.3 [7.2], 57.8% female) with self‐reported SCD. We assessed global cognitive functioning, memory, concentration, planning, and reasoning using the computer‐based Cambridge Brain Sciences battery. Assessment of 24‐hour BP was performed using an automated, ambulatory BP monitoring device (SpacelabsModel 90207). Ambulatory BP was measured every 30 minutes between 6am and 10pm, and hourly between 10pm and 6am. We employed hierarchical regression models to examine associations between 24‐hour systolic BP and cognition. Further, we conducted ANCOVAs exploring dose‐response relationships by stratifying our sample using clinical cut‐offs for normal (≤120 mmHg, n = 52), preclinical (121 to 135 mmHg, n = 119), and hypertensive (>135 mmHg, n = 59) BP. All analyses were adjusted for age, sex, MoCA, years of education, and diagnosis of diabetes and/or hypertension.ResultIn our sample, 24‐hour systolic BP was negatively associated with reasoning scores (unstandardized B [95% CI] = ‐0.008 [‐0.016 to ‐0.001], R2Change = 0.016, p = 0.028). The dose‐response analysis revealed a main group effect (F[2,221] = 3.6, p = 0.029, ηp2= 0.032), with post‐hocpairwise comparisons indicating that individuals with normal BP levels outperformed those with preclinical (mean difference [95% CI] = 0.280 [0.068 to 0.492], p = 0.010), and hypertensive (0.265 [0.021 to 0.508], p = 0.034) BP levels. The tasks adopted to assess reasoning targeted specifically grammatical reasoning, conflict resolution, and deductive reasoning, which fall under the overall scope of executive function tasks. No other relevant associations or interactions were found.ConclusionIn this sample of older adults with SCD, 24‐hour systolic BP levels above optimal clinical parameters were negatively associated with cognitive reasoning performance. Future research should investigate whether interventions that target BP control could mitigate impairment on reasoning performance.