bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cholinergic network disruption in AD subtypes: A study using graph theory
Authors: Gonzalez‐Burgos Lissett , Grothe Michel , Teipel Stefan J. , Westman Eric , Ferreira Daniel 
Published: December 2020

AbstractBackgroundCholinergic dysfunction is central in Alzheimer’s disease (AD). Recent advances in neuroimaging techniques and availability of larger postmortem datasets have opened new opportunities to understand the role of the cholinergic network in AD pathogenesis. However, there is pathophysiological heterogeneity within AD. AD subtypes with different distribution of neurofibrilary tangles, regional atrophy, and network disruption have been revealed in neuropathological and structural magnetic resonance imaging (sMRI) studies. We aimed to identify the cholinergic network using graph theory on sMRI data, and investigate whether differential cholinergic network disruption underlies the subtypes of AD.MethodWe applied graph theoretical analysis to structural MRI data from 75 Ab‐positive AD patients and 64 Ab‐negative controls from ADNI‐1. AD patients were classified into three subtypes according to Murray et al., (2011): typical AD, limbic‐predominant and hippocampal‐sparing. We built brain structural networks from 68 cortical regions and 14 subcortical gray matter structures. Network disruption was investigated through modular analyses by applying the Newman algorithm on weighted graphs.ResultWe identified 43 AD patients with a brain atrophy pattern consistent with typical AD; 17 patients with a limbic‐predominant pattern; and 15 patients with a hippocampal‐sparing pattern. We identified the cholinergic network in healthy controls, which included the basal forebrain, medial temporal lobe, precuneus, lateral parietal and occipital cortex, basal ganglia and thalamus. This network was completely fragmented in AD patients, but disruption differed according to subtype. The basal forebrain retained correlations only with basal ganglia and medial temporal lobe regions in typical AD; while in hippocampal‐sparing and limbic‐predominant subtypes these correlations also extended to new regions in frontal and lateral temporal cortices.ConclusionGraph theory on sMRI is able to identify a cholinergic network similar to that previously described in postmortem and in vivo diffusion imaging studies. AD subtypes have a distinct signature of cholinergic network disruption largely associated to their atrophy patterns. It is thus possible that pathology targeting the cholinergic system is one of the factors contributing to the emergence of these distinct subtypes. Our results may help to further understand pathophysiological heterogeneity in AD, with potential applications to research, clinical work and drug decision.
Orderings of biomarker changes for Alzheimer disease in cognitively normal individuals from 18 to 101 years of age
Authors: Xiong Chengjie , Luo Jingqin , Masters Colin L , Johnson Sterling C. , Albert Marilyn S. , McDade Eric , Fagan Anne M. , Benzinger Tammie L.S. , Hassenstab Jason , Cruchaga Carlos , Bateman Randall J. , Morris John C. 
Published: December 2020

AbstractBackgroundThe temporal orderings of pathologic biomarker changes during preclinical AD have been hypothesized graphically, incorporated into diagnostic criteria of preclinical AD, and further extended to the A/T/N framework. These hypotheses, however, remain to be rigorously and statistically tested.MethodsBiomarker and cognitive data were harmonized across eight ongoing longitudinal studies: 1) Washington University (WU) Adult Children Study; 2) Johns Hopkins University Biomarkers for Older Controls at Risk for Dementia Study; 3) Wisconsin Registry for Alzheimer's Prevention; 4) Australian Imaging, Biomarkers and Lifestyle Study; 5) WU Dominantly Inherited Alzheimer Network; 6) WU Healthy Aging and Senile Dementia study; 7) WU Knight Alzheimer Disease Research Center (ADRC); and 8) Wisconsin ADRC. Cerebrospinal fluid (CSF) analytes, molecular imaging of cerebral fibrillar β‐amyloid with positron emission tomography (PET) using the [11C] benzothiazole tracer, Pittsburgh Compound‐B (PIB), magnetic resonance imaging (MRI)‐based brain structures, and clinical/cognitive outcomes for 3284 cognitively normal individuals aged 18 to 101 years, were analyzed. The age at which each marker exhibited an accelerated change (called the change‐point) was estimated by piecewise regression models, and compared across the markers by bootstrapping.ResultsAccelerated changes in CSF Aβ1‐42 (Aβ42) occurred at 48.28 years of age, followed by PET PIB mean cortical standardized uptake value ratio (SUVR) with a change‐point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change‐point at about 60 years, similar to those for MRI hippocampal volume and cortical thickness. The change‐point for a cognitive composite occurred at 62.41 years. The change‐point for CSF Aβ42, albeit not significantly different from that for PIB SUVR, occurred significantly earlier than that for CSF Tau and Ptau, MRI markers and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other.ConclusionsThese findings support the hypothesized early changes in amyloid in preclinical AD, and further suggest that changes in neuronal injury and neurodegeneration markers occur close in time to each other and to cognitive decline. These results have important implications for the design and analysis of future prevention trials in AD.
A pilot multiple crossover, randomized controlled trial of methylphenidate in mild cognitive impairment using standardized tests and daily brain games to track cognition
Authors: DesRuisseaux Libby A. , Williams Victoria J. , McManus Alison J. , Gupta Anoopum S. , Bolling Anna M. , Schwab Nadine A. , Riley Misha M. , Carlyle Becky C. , Azami Hamed , Gerber Jessica A. , Betensky Rebecca A. , Arnold Steven E. 
Published: December 2020

AbstractBackgroundConventional clinical trial design in AD and AD‐related disorders (ADRD) is the parallel‐group randomized controlled trial. However this design requires large sample sizes to detect meaningful effects in an "average" patient. They are costly, and have not yielded new treatments for many years. As an alternative, the multi‐crossover, randomized control trial (MCRCT) is a design in which patients serve as their own control across successive, randomized blocks of active treatment and placebo. This design overcomes many limitations of a parallel group trial, yielding unbiased assessment of individual treatment effects ("N‐of‐1") regardless of unique patient characteristics. The goal of this study is to pilot a MCRCT of a potential symptomatic treatment, methylphenidate, for mild‐stage AD/ADRDs, testing feasibility and compliance of participants in this design and efficacy of the drug using standard and novel outcome measures suited for this design.MethodsTen participants with mild cognitive impairment or mild‐stage dementia due to AD/ADRDs will undergo a four‐week lead‐in period followed by three, month‐long treatment blocks (two weeks of treatment with methylphenidate, two weeks placebo in random order). The primary outcome of interest is cognition, measured using standard office‐based assessments at the end of each treatment period and daily home‐based brain games played throughout the study. Secondary and exploratory outcomes include neuropsychiatric and functional assessments, actigraphy, and other novel digital cognitive and neurophysiological assessments.ResultCurrently, five participants (three male, mean age = 65.6, mean education = 17.6 years, mean MoCA = 23/30) have been screened and randomized. Preliminary interim analyses are ongoing.ConclusionThis pilot study will gauge feasibility of conducting a MCRCT trial for symptomatic treatment in early AD/ADRDs, compare home‐based daily brain games with standard office‐based cognitive measures, and explore practicability and potential utility of novel digital phenotyping tools within a clinical trial for AD/ADRD. Particular attention will be paid to compliance, tolerability of drug and participation, learning effects, trends and stability of daily measures across blocks, medication carryover effects, and correlations between home and office‐based assessments. These data will provide guidance for more efficient trial design and use of potentially more robust, ecological outcome measures in AD/ADRD research.
Cognitive and psychosocial predictors of everyday function
Authors: Farias Sarah Tomaszewski , Eng Chloe W. , Chan Michelle L. , Gilsanz Paola , Whitmer Rachel A. 
Published: December 2020

AbstractBackgroundSubtle declines in functional abilities, including difficulties completing instrumental activities of daily living (IADLs; e.g., managing finances), can be very early indicators of Alzheimer’s Disease and related disorders (ADRD). Cognitive difficulties are major determinants of IADL difficulties, but account for less than half the variance in performance. Psychosocial variables, such as depression, loneliness, and perceived emotional support may also influence a person’s functional status independent of their cognition. The present study examined cognitive and psychosocial predictors of IADL functioning across an ethnoracial diverse cohort.MethodThe Kaiser Healthy Aging and Diverse Life Experience (KHANDLE) cohort is comprised of Kaiser Permanente Northern California members (approximately even proportions of Caucasians, African Americans (AA), Asians, and Latinos) who are age ≥65, without a diagnosis of cognitive impairment or dementia, and who participated in Multiphasic Health Checkups between 1964‐1977. At enrollment, participants completed a self‐report measure of IADL, neuropsychological testing measuring memory and executive functioning, and psychosocial questionnaires measuring depression, loneliness, and emotional support. Analyses include 1, 485 participants (448 Caucasian (30.2%), 386 AA (26.0 %), 362 Asian (24.4%), and 289 Latino (19.5%). Cox proportional hazards models estimated the associations between psychosocial factors and cognitive domains overall and within ethnoracial groups.ResultAverage baseline age was 75.6 and 59.6% were female. AA were less likely to report excellent/very‐good heath (30.1%) verses Caucasians (50.4%), Asians (45.0%), and Latinos (45.3%). After controlling for age, education, gender, and self‐rated health, loneliness predicted IADL performance independent of both memory (p<0.0001) and executive functioning (p<.0001). Emotional support predicted IADLs, independent of memory (p=0.0048) and executive functioning (p=0.0098). Depression was not independently associated with IADLs. Relationships were similar across the four ethnoracial groups.ConclusionFew studies have simultaneously examined cognitive and psychosocial predictors of IADLs across such a diverse group of older adults. Our study indicates that greater loneliness and lower perceived emotional support are associated with worse IADL function, independent of cognitive performance across ethnoracial groups. While the directionality of these relationships need further study, interventions aimed at decreasing social isolation may ultimately help to keep individuals functioning more independently in their daily lives.
APOE4, lifestyle factors, and cognitive decline: A population‐based cohort study
Authors: Dhana Klodian , Aggarwal Neelum T , Rajan Kumar B , Barnes Lisa L , Evans Denis A , Morris Martha Clare 
Published: December 2020

AbstractBackgroundWhile prevention trials are recruiting individuals at high risk of dementia, including those who are genetically predisposed, it has become uncertain whether these interventions, in particular, lifestyle factors can lessen the increased genetic risk. We investigated whether the association between lifestyle factors and cognitive decline differed as a function of APOE4 status in an elderly population.MethodUsing data from the Chicago Health and Aging Project, a population‐based cohort study, we defined a healthy lifestyle score based on non‐smoking, >=150 min/week moderate/vigorous physical activity, light‐to‐moderate alcohol consumption, high‐quality MIND diet, and engagement in late‐life cognitive activities, yielding an overall composite score that ranged from 0 to 5. Global cognitive function was assessed using brief tests of episodic memory, executive function, and the MMSE in approximately 3‐year cycles for over 18‐years. We examined the association of adherence to lifestyle factors with cognitive decline separately in those with and without APOE4 using a linear mixed effect model adjusted for age, sex, education, race, cardiovascular disease, time, and their interactions with time.ResultOf 3,886 older adults included in the study, 1,269 (33%) were APOE4 carriers. Compared to non‐carriers, APOE4 carriers were younger (71y vs. 72y; p<0.001), mostly African American (68% vs. 57%; p<0.001), and had a lower global cognitive score at baseline (0.37 vs. 0.43; p=0.01). In the multivariable‐adjusted model, a higher healthy lifestyle (4‐5 healthy lifestyle factors versus 0‐1 factor) was associated with a slower rate of cognitive decline in both carriers (beta=0.029; p<0.001) and non‐carriers (beta=0.011; p=0.013). However, when we created a propensity score‐matching sample where groups with and without APOE4 were not different concerning age, gender, race, education, baseline global cognitive score, and sample size, these associations differed by APOE4 status. In the matched sample, adherence to a healthy lifestyle was not associated with a cognitive decline in non‐APOE4 carriers (beta=0.002; p=0.763) but remained significant in APOE4 carriers (beta=0.046; p<0.001).ConclusionA healthy lifestyle should be promoted to everyone, especially to individuals with a genetic predisposition for Alzheimer’s dementia.
The aetiology of frontal white matter lesions in Alzheimer’s disease are associated with both neurodegenerative and ischemic mechanisms
Authors: McAleese Kirsty E. , Miah Mohi , Graham Sophie , Baker Georgie , Walker Lauren , DeCarli Charles , Koss David , Attems Johannes 
Published: December 2020

AbstractBackgroundWe have previously shown that the pathogenesis of parietal white matter lesions (WML) seen in Alzheimer’s disease (AD) can be associated with degenerative loss as a result of Wallerian degeneration activated by hyperphosphorylated tau (HPτ) [1]. In a subset of these cases, we investigated the the pathological composition and aetiology of WML from the frontal region.MethodFrontal WML from 40 post‐mortem brains (AD, n=19; controls, n=21) were quantitative assessed for WML severity, axonal loss and demyelination, as well cortical measures of HPτ, amyloid‐beta (Aβ) and WM‐small vessel disease (SVD) score. Biochemical assessment included the Wallerian degeneration‐associated protease calpain and the ratio of myelin‐associated glycoprotein (MAG) and proteolipid protein (PLP) as a measure of hypoperfusion.ResultNo significant difference was revealed in WML severity between controls and AD. WML severity was associated with axonal and myelin loss in AD (both P<0.02), but only myelin loss in controls (P<0.0001). WML severity correlated with WM‐SVD score in both controls (P<0.0001) and AD (P <0.05); no association between WML severity and HPτ was revealed in the AD group. Calpain was increased in AD but this was not significant, and calpain correlated with Aβ (P<0.05). No significant difference was seen in MAG:PLP between AD and controls.ConclusionFrontal WML in AD are likely influenced by both ischemic and degenerative mechanisms in contrast to the posterior WM that has a prominent degenerative influence. This study highlights important regional differences in the pathogenesis of WML that may be diagnostically relevant. (1) McAleese et al (2017) DOI 10.1007/s00401‐017‐1738‐2
Longitudinal factors associated with living well outcomes in people with mild‐to‐moderate dementia: Initial findings from the IDEAL cohort
Authors: Matthews Fiona E , Gamble Laura , Clare Linda ,   the IDEAL Study Research Group
Published: December 2020

AbstractBackgroundUnderstanding the factors associated with quality of life (QoL), satisfaction with life (SwL) and wellbeing can help us become more effective in optimizing the potential for people with mild‐to‐moderate dementia to ‘live well’ with the condition. Identifying individuals at risk of declining well‐being could help to target support more appropriately, but there is little evidence available about factors that may influence ability to ‘live well’ longitudinally.MethodsWe used longitudinal data from 1547 individuals with mild‐to‐moderate dementia participating in the IDEAL cohort, who have been assessed on entry and followed up 12 months and 24 months later. We examined how factors found to be important at baseline were associated with change over time using growth curve modelling. Factors were grouped into four domains: psychological characteristics and health; physical health; social capitals, assets and resources; and functional ability.ResultsPsychologically, individuals who were less depressed and lonely, and had positive attitudes to ageing, had better QoL, SwL and wellbeing over three waves. Decreasing loneliness was associated with increasing QoL and Wellbeing, increasing depression with decreasing SwL, and a decrease in their attitude to ageing less wellbeing over time. Physically, better self‐rated health, sleep quality, eyesight, hearing, appetite and olfaction predict better QoL and wellbeing, and all but olfaction predict better SwL, over the 3 waves. Socially, less isolation, greater cultural capital and greater reciprocity and trust in the local neighbourhood predict better QoL, SwL and wellbeing over the 3 waves. Good functional ability was associated with better QoL, SwL and wellbeing over the 3 waves.ConclusionsUsing longitudinal data showed remarkable consistency with different methods of measuring how people with dementia “live well”. Understanding these longitudinal changes is vital to identify potential factors for intervention.
A loss of neuronal inhibition best explains EEG abnormalities in preclinical Alzheimer’s disease: A multiscale computational modeling study
Authors: van Nifterick Anne M. , Gouw Alida A. , Scheltens Philip , Stam Cornelis J. , de Haan Willem 
Published: December 2020

AbstractBackgroundA better understanding of the earliest functional brain changes in human preclinical Alzheimer’s Disease (AD) may improve diagnosis and intervention. Evidence accumulating from experimental neurophysiological research illustrates that neuronal excitation/inhibition imbalance is an early sign of AD (Palop and Mucke, 2016). However, how this microscale phenomenon relates to the typical changes in oscillatory activity during preclinical AD stages at the macroscale as assessed by electroencephalography/magnetoencephalography (EEG/MEG), remains unclear. This computational modeling study of a network of coupled neural masses aims to find the most probable pathophysiologic mechanism by linking the microscopic level of neurons with the macroscopic level of observable human brain dynamics.MethodThe brain dynamics simulation model consists of 78 neural mass models (describing regional brain activity), coupled according to human DTI‐based structural network topology (Ponten et al., 2010). The model produces EEG‐like data that can be analyzed the same way as patient recordings. We first examined the effect of gradually increasing or decreasing global excitability of either inhibitory or excitatory neurons on overall oscillatory behavior (average total and relative power, peak frequency and spike density), by changing the average membrane threshold potential. Consequently, these four different scenarios were compared with (CSF) amyloid‐positive mild cognitively impaired (MCI) patient data (Gouw et al., 2017) to identify the most compatible underlying mechanism.ResultThe results confirm previous literature (Isaacson and Scanziani 2011), showing an overall stronger effect of changes to inhibitory neurons on oscillatory activity compared to excitatory neurons. Simulating a decrease in inhibition of the network is associated to a reduction in peak frequency, lower relative alpha power and higher relative theta power, which best matches to preclinical AD data (Gouw et al., 2017). The decreased inhibition scenario resulted furthermore in a strong increase in total power and the highest spike density levels.ConclusionThis study provides theoretical support for the hypothesis that inhibitory (inter)neuron dysfunction is one possible mechanism underlying cortical oscillatory activity changes and a hyperactive network in early AD, in line with recent insights from experimental animal studies.
Revisions and updates to the Everyday Cognition (ECog) scales
Authors: Farias Sarah Tomaszewski , Huss Olivia , Chan Michelle L. , Ruiz Rene 
Published: December 2020

AbstractBackgroundAccurate and reliable assessment of everyday functional abilities among older adults is important in clinical and research settings. The Everyday Cognition scale (ECog) was designed over a decade ago to measure early everyday functional limitations across multiple domains: Everyday Memory, Language, Visuospatial Abilities, Planning, Organization, and Divided Attention. The ECog has been shown to be sensitive to early detection of neurodegenerative disease such as Alzheimer’s, and in tracking disease progression. The goal of the current study was to update the content of the ECog and ensure its culturally applicable to diverse older adult populations.Method42 individuals were included in the study. Participants included older adults with and without Mild Cognitive Impairment (MCI) and their informants/study partners. 66% of the sample was of an ethnic minority. We utilized iterative cognitive interviewing methods to examine the understandability and cultural relevance/applicability of ECog items. This information was then used to modify existing items, delete poor items, and develop new items as needed. Two rounds of interviews were completed with older adults and informants. The purpose of Round 1 was to inform the revision of existing items and elicit new items. The purpose of Round 2 was to confirm the understandability of items revised or produced from Round 1. All interviews were transcribed verbatim and analyzed using standard qualitative methods.ResultBased on analysis of interview feedback, instructions to the ECog were modified slightly to emphasize current performance is being compared to an individual’s own baseline level of function. Response options remained primarily unchanged from the original version. When evaluating each of the individual items, participant feedback lead to 15 of the 39 original items being revised to improve item clarity and understandability. A total of 4 items were deleted;3 due to outdated content (e.g., using a map, balancing a checkbook) and 1 because it was vague. A total of 6 entirely new items were developed, primarily to cover more contemporary activities (e.g., use of technology).ConclusionThe final revised ECog includes 41 items. Future work will validate the revised ECog by measuring it in association with neuropsychological performance, external measures of disease, and other functional measures.