bluuebunny/crossref_metadata_2025_split huggingface dataset:
White Matter Hyperintensity and PET‐Based Amyloid Load Correlations: A Meta‐Analysis
Authors: Bauer Kacie , Malek‐Ahmadi Michael H. 
Published: December 2022

AbstractBackgroundWhite matter hyperintensities (WMHs) are prevalent vascular pathologies that often co‐occur with amyloid plaque deposition in Alzheimer’s disease (AD). Previous research has shown that antemortem WMHs correlate well with post‐mortem findings of cerebral amyloid angiopathy (CAA). PET‐amyloid imaging is widely used to assess in‐vivo amyloid load, however the extent to which CAA‐binding of amyloid tracers contributes to global measures of amyloid load is unclear. The aim of this meta‐analysis was to determine the strength of the correlation between amyloid load and WMHs in AD subjects.MethodThirteen studies that reported either a correlation or regression coefficient between amyloid load and WMHs were included. Age, education level, sample size, correlation, study setting (community, clinic, Alzheimer’s Disease Neuroimaging Initiative [ADNI]), amyloid tracer type (florbetapir vs. Pittsburgh compound B [PiB]), and method of WMH quantification (visual vs. volumetric) were extracted. Random effects results were reported for the main and subgroup analyses. Between‐study heterogeneity was quantified using I2 with 95% confidence intervals.ResultThe overall correlation for amyloid load and WMH load was r=.25, 95% CI[.15, .35], p<.001; I2=80%, 95% CI[66%, 88%]. The combined effect size of community and clinic‐based studies (r =0.30) was larger than that of ADNI studies (r=0.21) and had substantially less heterogeneity (I2=67% vs. I2=86%). Florbetapir had a stronger correlation with WMHs (r=0.28) than PiB (r=0.20), with less heterogeneity (I2=71%, I2=87%). Visual methods of WMH quantification yielded a stronger correlation with amyloid load (r=0.38) than volumetric methods (r=0.20), however between‐study heterogeneity was similar for both methods (I2=80%, I2=82%).ConclusionWMHs correlate significantly with amyloid load, but this relationship is strongly influenced by amyloid tracer type and WMH quantification method. A high level of heterogeneity was noted for ADNI studies which further indicates the impact that methodologic and analytic techniques may have on a study’s findings. Although CAA‐related binding cannot be distinguished from parenchymal binding in amyloid‐PET studies, these results provide a general estimate of CAA’s contribution to PET‐based estimates of global amyloid load.
Carotid intima media thickening is associated with higher future amyloid‐ß burden
Authors: Baradaran Hediyeh 
Published: December 2022

AbstractBackgroundCarotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid‐ß (Aß) burden. We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aß on 11C‐Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aß burden.MethodWe studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5± 5.7 years) and an average of 9.6 years later at exam 8, and PiB imaging measuring Aß on average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow‐up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aß in brain regions associated with Alzheimer’s disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors.ResultParticipants with higher mean ICA IMT had more Aß in the precuneus (beta ± standard error [SE]: 0.264 ± 0.12, p = 0.034) and the FLR regions (SE: 0.155 ± 0.071, p = 0.034), after adjusting for age, sex, and vascular risk factors. We did not find an association between any CCA IMT measures and Aß or progression of ICA or CCA IMT and Aß.ConclusionCarotid atherosclerosis, as measured by ICA IMT, is associated with increased Aß burden later in life. These findings support a link between vascular disease and AD/ADRD.
Discovery and validation of dominantly Inherited Alzheimer’s Disease mutations in populations from Latin America.
Authors: Llibre‐Guerra Jorge J , Takada Leonel Tadao , Verson Carmen Alaez , Burgute Bhagyashri , Nitrini Ricardo , Sosa‐Ortiz Ana Luisa , Castilhos Raphael Machado , Chaves Marcia L Fagundes , Ibarrola Mariana Longoria , Carrillo‐Sanchez Karol , Brucki Sonia Maria Dozzi , Flores‐Lagunes Luis Leonardo , Molina Carolina , Olivares Marcos Jimenez , Ziegemeier Ellen , Goate Alison M. , Cruchaga Carlos , Renton Alan E. , Fernandez Maria Victoria , Day Gregory S , McDade Eric , Bateman Randall J. , Karch Celeste M. 
Published: December 2022

AbstractBackgroundMore than 300 variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes have been reported to cause Dominantly Inherited Alzheimer Disease (DIAD). However, most of these reports come from non‐Hispanic whites and the full extent of DIAD remains understudied in Latin American (LatAm) countries. Here we describe five AD affected families from LatAm carrying novel DIAD variants.MethodsFive novel variants in the presenilin1 (PSEN1) gene were identified in Brazilian (p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se and p.Ala275Thr) and Mexican families (p.Ile414Thr). To assign the likelihood of pathogenicity among these variants of unknown significance, we report pedigree information, frequency in control populations, in silico predictions, and cell‐based models.ResultThe mean age at onset in newly identified families was 43.5 years (range 36‐54). The novel variants were absent from gnomAD genome and exome databases. Two PSEN1 variants (p.Val103_Ser104delinsGly and p.Lys395Ile) showed segregation with the disease status; segregation studies were not possible in the other three families. Additionally, PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr produced Aβ profiles consistent with known AD pathogenic mutations (i.e. increased extracellular Aβ42/40); thus, we consider them as likely pathogenic. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation; therefore, PSEN1 p.Ile414Thr likely represents an AD risk factor or benign polymorphism.ConclusionOur study provides further insights into the genetics of AD in LatAm by identifying novel DIAD pathogenic variants in Brazil and Mexico, two countries with distinct genetic admixtures. Expanding the families eligible to participate in observational and clinical trials of DIAD enhances the generalizability of diagnosis and treatment approaches.
How is semantic memory affected in Mild Cognitive Impairment?
Authors: Delage Emilie , Chasles Marie‐Joëlle , Cole Jessica , Rouleau Isabelle , Joubert Sven 
Published: December 2022

AbstractBackgroundMild cognitive impairment (MCI) is a condition considered by many as a transitional stage between healthy aging and Alzheimer’s disease. Although its diagnosis is typically based on the assessment of episodic memory, evidences show that impairment in semantic memory would be one of the first manifestations of cognitive impairment. This study aims to investigate how semantic memory is affected in MCI. Precisely, we will explore if core memory of common knowledge is impaired in MCI, and if the performance in semantic memory task vary with the modality of presentation of the stimuli (verbal vs visual).MethodA group of healthy people aged between 60 and 90 years old (mean: 77.4 N = 43), and a age‐matched group meeting the criteria for MCI (N = 32), who have lived in Quebec (Canada) for at least 30 years, completed two neuropsychological tests evaluating the semantic memory of famous people, which have been proven to be the most sensible way to detect even subtle variation in semantic memory.ResultResults indicate that performance in both tests is impaired in the MCI group, compared to the healthy elderly group. This means that the MCI group have more difficulty to name famous people (t (69) = 5,173, p < 0.01), as well as answer basic questions on them (ex: their profession, nationality, etc.), when presented from their picture (t (69) = 4.849, p < 0.01) or their name (t (65) = 3.488, p < 0.01), compared to healthy people of the same age. There was no difference between their performances when the stimuli was presented in the visual or verbal modality (t (30) = 0.928, p > 0.05).ConclusionThis study demonstrates that semantic memory of famous people is impaired in MCI, and that impairment affects the capacity to name famous people as well as remembering facts about them. In addition, there are no difference if the stimuli are presented visually or verbally. This suggests that the impairment in semantic memory in MCI is due to a degradation of the memory, and is not modulated by other cognitive functions or modality.
High Cardiorespiratory Fitness Exerts a Neuroprotective Effect Against Obesity, Regardless of Lifestyle Modification
Authors: Pantiya Patcharapong , Thonusin Chanisa , Ongnok Benjamin , Chunchai Titikorn , Sumneang Natticha , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: December 2022

AbstractBackgroundHigh cardiorespiratory fitness (CRF) and behavioral modification exert a neuroprotective effect in obese condition. However, the interplay between CRF, obesity, and behavioral modification has never been identified. Therefore, this study investigated whether high CRF level provides the neuroprotective effect in obese rats receiving either caloric restriction or exercise.MethodSeven‐week‐old male Wistar rats were fed with either a normal diet (ND; n = 5) or a high‐fat diet (HFD; n = 25) to induce obesity for 12 weeks. At the end of week 12, baseline CRF was measured. The ND‐fed rats were continuously fed with a ND for an additional 16 weeks. The HFD‐fed rats were randomly assigned into 5 groups (n = 5/group) to receive either 1) a HFD without intervention for 16 weeks, 2) 40% caloric restriction for 6 weeks followed by an ad libitum ND for 10 weeks (short‐term caloric restriction followed by weight maintenance), 3) 40% caloric restriction for 16 weeks (long‐term caloric restriction), 4) a HFD plus an exercise for 6 weeks followed by a ND without exercise for 10 weeks (short‐term exercise followed by weight maintenance), or 5) a HFD plus an exercise for 16 weeks (long‐term exercise). At the end of interventions (week 28), CRF and cognitive function were determined. After that, the rats were euthanized for molecular studies in the brain.ResultThere was a significantly positive correlation between running distance at week 12 and week 28 (Figure A), indicating that CRF is highly intrinsic factor. When compared to the ND‐fed rats, CRF level was lower in the obese rats at week 12 (Figure B). At week 28, all types of behavioral modification significantly increased the CRF level in obese rats (Figure C). Interestingly, high baseline CRF level demonstrated a significant correlation with favorable brain profiles at follow‐up in obese rats, both with and without behavioral modification (Figure D).ConclusionRegardless of behavioral modification, high CRF exerts a neuroprotective effect against obesity. Hence, targeting on an enhancement of CRF may provide the better effective therapy for obesity‐induced neuronal impairment.
User‐centered design to examine interaction of people with MCI or dementia with smartwatches: the SAMi intervention study framework
Authors: Rong Eleonora , Köhler Stefanie , Bieber Gerald , Teipel Stefan , Goerss Doreen 
Published: December 2022

AbstractBackgroundAssistive technologies show promising features to support people with cognitive impairment in daily life, e.g. mobile sensors for falls detection. But adoption of the rapidly evolving technologies is still limited in practice. We applied user‐centered design to investigate factors contributing or hindering successful interventions on smartwatches.MethodsWe previously presented data from qualitative studies which analyzed values and needs for assistive technologies. In this subsequent study, we included patients with MCI and dementia. To prevent participants from feeling overwhelmed, we accompanied participants during a test intervention (0). Patients’ reactions to the following two tasks delivered by the smartwatch were observed remotely via cameras: A) drinking some water, as a task related to nursing and B) circling bells on a worksheet, as an occupational task. We also implemented two different intervention‐intensities: 1) regular and 2) intensive, with respect to vibration, alarm sounds and instructions. User feedback was obtained with questionnaires. Here, we present data of the feasibility analysis after completion of n = 20 patient, randomly assigned to intensity level 1 or 2 (n = 10/10). All patients were confronted with both tasks in the respective intensity, repeated up to three times in case of failure.ResultsAs result of discussions in interdisciplinary working groups, we decided for a “wizard‐of‐oz setting”, which means controlling the smartwatch manually by a smartphone used as remote control. Systematic debriefing revealed obstacles in all study phases. On user side the problem of varying use of glasses and hearing aids couldn’t be overcome. On the technical side pairing problems (connection of phone and watch), automatically reduced brightness of smartwatch display and complicated maintenance of hardware were critical problems. Patients were committed to give feedback and felt not stressed due to the study. Still, filling in the questionnaires with Likert scales was challenging for many participants due to alternation of positively and negatively worded items.ConclusionStudying effects of smartwatch‐based interventions in patients with cognitive decline with user‐centered design requires intensive interdisciplinary work. Comparison of the video‐taped, observed behavior with self‐reported behaviors in questionnaires might elucidate chances and limits of user‐centered approaches and will be our next objective.
Lipidome Profiling of APOE4 AD brains implicated unresolved neuroinflammation involving polyunsaturated fatty acid metabolism
Authors: Asante Isaac , Ebright Brandon , Wang Shaowei , Poblete Roy , Arvanitakis Zoe , Bennett David A , Louie Stan G , Yassine Hussein N. 
Published: December 2022

AbstractBackgroundThe Apolipoprotein E4 (APOE4) allele has been associated with an accentuated response to brain inflammation and increases the risk of AD dementia progression. Among inflammation signaling pathways, eicosanoids play a prominent role in neurodegeneration.MethodThis study compared measures of the eicosanoid lipidome from patients with AD dementia compared to age and sex‐matched controls with no cognitive impairment (NCI), stratified by APOE genotypes using postmortem brain tissues from the Religious Order Study (n = 42).ResultTargeted lipidomic analysis by mass spectrometry of the dorsolateral prefrontal cortex demonstrated lower levels of omega‐3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA), and DHA‐derived neuroprotectin D1 (NPD‐1) in persons with lower global cognitive function, independent of age, sex and education years. APOE4 was associated with greater pro‐inflammatory lipids (e.g., PGD2, PGE2, 12‐HHT, LTB4 and 5‐HETE) and pro‐resolving lipids (eg. lipoxins, resolvins and EETs) in patients with dementia (Figure 1). Pathway analysis implicates greater activation of calcium dependent phospholipase A2 (cPLA2), 5‐lipoxygenase (5‐LOX) and soluble epoxide hydrolase (sEH) underlying the observed lipidomic profile.ConclusionThese results confirm a chronic state of unresolved inflammation in the AD dementia brain that is accentuated in carriers of the APOE4 allele and identify novel therapeutic targets.
Brain Controllability of Cognitive Control Networks is Associated with Executive Functions in Older Adults
Authors: Tang Rongxiang , Elman Jeremy A. , Franz Carol E , Hagler Donald J. , Puckett Olivia K. , Kremen William S. 
Published: December 2022

AbstractBackgroundExecutive functions encompass effortful top‐down cognitive processes crucial for daily functioning. They are particularly vulnerable to aging in older adults and are often affected early in the course of Alzheimer’s disease. However, the neural mechanisms underlying aging‐related decline in executive functions are not well understood. Modal controllability is a structural metric quantifying the ease at which brain regions can move the brain into difficult‐to‐reach states with substantial effort to support diverse cognitive processes. The emphasis on effortful state transitions bears strong similarity to the definition of executive functions as effortful cognitive processes, rendering modal controllability as a putative neural substrate of executive function. Controllability has been associated with cognitive performance in younger populations, but no studies have examined controllability in older adults or its association with executive function over time.MethodWe used diffusion MRI (dMRI) data from community‐dwelling men ages 56‐70 (N=264 Time 2, N=104 Both Time 1 & 2) in the Vietnam Era Twin Study of Aging (VETSA).We performed whole‐brain deterministic fiber tracking on dMRI data to reconstruct white matter streamlines, which were then used to build structural connectivity matrices. Network‐level modal controllability of two cognitive control networks (multiple demand system and control network) were computed from connectivity matrices. An executive function factor score was computed based on six well‐established neuropsychological tasks: Stroop, Trail Making Test, Category Switching, Letter‐Number Sequencing, Reading Span, and Digit Span.ResultsIn cross‐sectional analyses controlling for age, health status, ethnicity, and young adult general cognitive ability, modal controllability of cognitive control networks was positively associated with executive function at Time 2. Change in controllability from Time 1 to Time 2 (∼6 years) was positively associated with change in executive function over the same period.ConclusionFindings suggest that a putative mechanism of cognitive aging may involve the controllability of structural networks in supporting brain functional dynamics necessary for cognition. In particular, the longitudinal association suggests that structural network changes in controllability may be a key mechanism underlying aging‐related decline in executive function. A next step will be to how such changes are related to risk for mild cognitive impairment and Alzheimer’s dementia.
Baseline hippocampal vascular reactivity predicts conversion to mild cognitive impairment: an analysis of the SPRINT‐MIND study
Authors: Aslanyan Vahan , Ortega Nancy E , Williamson Jeff D. , Mack Wendy J , Pa Judy 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is characterized by gradual decline to mild cognitive impairment (MCI) and dementia. Vascular risk factors contribute to cognitive decline suggesting that maintaining cerebrovascular health could slow disease progression. Vascular reactivity, a measure of blood vessel elasticity and arterial stiffness, provides a quantitative neurobiological measure of cerebrovascular health. In the present study, we hypothesized that higher hippocampal and whole‐brain gray matter vascular reactivity would be associated with lower rate of conversion to MCI.Method518 participants enrolled in Systolic Blood Pressure Intervention Trial Memory and Cognition in Decreased Hypertension (SPRINT‐MIND) study were selected for the current analyses. Participant structural MRI and vascular reactivity measures were included in the current analyses. Vascular reactivity was derived from a 16‐second breath‐holding BOLD fMRI scan. MCI conversion was determined by an expert panel from cognitive assessments. Cox proportional hazards model was used to test if disease progression was associated with hippocampal or whole‐brain gray matter vascular reactivity adjusting for age, sex, education, and treatment assignment (intensive vs. mild BP control). Entorhinal cortex and parahippocampal gyrus control regions were also tested.ResultParticipant demographics are presented in Table 1. Median follow‐up was 5.36 years (IQR=2.11), median time‐to‐MCI was 2.04 years (IQR=0.46). Hippocampal vascular reactivity was significantly associated with conversion to MCI (hazard ratio (HR)=0.52 per 1% ΔCBF/1mm Hg CO2, 95% confidence interval (CI):(0.21,0.84)); this association did not differ by treatment group. Hippocampal volumes were also significantly associated with conversion to MCI (HR=0.58 per 1cm3, 95% CI:(0.36, 0.92)), but there was no correlation between vascular reactivity and volume, and hippocampal volumes did not confound the relationship between vascular reactivity and conversion. Whole‐brain gray matter vascular reactivity was associated with conversion to MCI (HR=0.60 per 1% ΔCBF/1mm Hg CO2, 95% CI:(0.42,0.86)). There were no associations between the control regions and conversion (HR(entorhinal cortex)=0.9 per 1% ΔCBF/1mm Hg CO2, 95% CI: (0.75,1.08); HR(parahippocampus)=0.96 per 1% ΔCBF/1mm Hg CO2, 95% CI: (0.90,1.01)).ConclusionBaseline hippocampal and whole‐brain gray matter vascular reactivity is associated with MCI progression, such that those with more vessel elasticity and less arterial stiffness converted to MCI at a significantly lower rate.
Effects of Histone Deacetylase Inhibitors on Different Memory Domains in an Animal Model of Aging and Alzheimer’s Disease
Authors: McClarty Bryan , Dong Hongxin 
Published: December 2022

AbstractBackgroundHistone deacetylases (HDACs) have been involved in regulation of memory and previous work from our group and others have shown promising beneficial effects of HDAC inhibitors (HDACis) in aging and neurodegenerative disorders, including Alzheimer’s disease. However, currently, there are no reports on cross comparison of none‐selective and selective HDACis for their beneficial effects on memory and AD‐like pathologies in both aging and AD models.MethodIn this study, 3‐, 12‐, and 18‐months of age WT and APP/PS1 mice were administered a broad acting HDACi valproic acid (VPA), and two selective Class 1 HDACis entinostat (MS‐275, targeting HDAC 1 and 3) and tacedinaline (CI‐994, targeting HDAC 1, 2 and 3) for 30 days. After HDACi administration, mice underwent three memory tests: the novel object recognition (NOR) for executive memory, Y‐maze for short‐term working memory, and Morris water maze (MWM) for long‐term spatial reference memory (n = 8‐10). After memory assessment, mouse prefrontal cortex and hippocampus were collected for biochemical studies.ResultWe found a decrease in executive memory, and long‐term spatial reference memory in WT mice at 18 months of age and, severe memory deficits of three memory domains in APP/PS1 mice at 12‐ and 18‐months of age, and most importantly, we found an age and genotype interaction in the severity of executive and long‐term spatial reference memory deficits in APP/PS1 mice. Both MS‐275 and CI‐994 rescued executive memory, and short‐term spatial reference memory, however, only CI‐994 was sufficient to rescue long‐term spatial reference memory in APP/PS1 mice. We also found a decrease in H3K9ac in APP/PS1 mice with aging at the gene promoters related to memory and synaptic plasticity, however, only CI‐994 rescued H3K9ac levels in APP/PS1 mice.ConclusionOur results suggest that selective HDACis could rescue memory function in APP/PS1 mice, and HDAC2 may be an important modulator for hippocampal dependent memory. We are continuing our investigation of changes of specific HDAC and histone acetylation marks on genes related to memory and synaptic plasticity in the hippocampus, but also in the PFC to identify regional specific of HDAC modulation across aging and AD.