bluuebunny/crossref_metadata_2025_split huggingface dataset:
The North Carolina Registry for Brain Health: An actionable strategy to include under‐represented groups in Alzheimer’s disease research
Authors: Welsh‐Bohmer Kathleen A , Plassman Brenda L , Kaufer Daniel , Byfield Grace , Price Stephen Russ , Ries Michelle G , Zolotor Adam J , McCart Michelle , Pulliam Amy , Silbersack Johanna , Byrd Goldie S 
Published: December 2020

AbstractBackgroundThe North Carolina Institute of Medicine (NC IOM), in response to a legislative mandate, convened a Task Force on Alzheimer’s Disease and Related Dementias (2015/2016) to develop an actionable strategic plan to address the state’s rising rate of Alzheimer’s disease and related dementias and to promote brain health. A recurring state appropriation supports the North Carolina (NC) Registry for Brain Health (Registry), an outcome of the task force plan.MethodsThe NC Registry for Brain Health aims to increase public awareness of dementia services, brain health research, and opportunities to participate in clinical investigations. A focus is on under‐served communities traditionally not included in research. The Registry includes investigators from collaborating institutions across the state, including Duke University, East Carolina University, North Carolina A&T State University, the University of North Carolina at Chapel Hill, and Wake Forest School of Medicine. Governance is provided by investigators from each of the collaborating institutions with input from NC IOM, NC DHHS and stakeholders throughout the state.ResultsPhase I of the project focused on establishing the Registry infrastructure, including governance, site identification and contracting, programming of the Registry database, and website development. Two public kick off events announcing the Registry were held in June 2019. Phase II has focused on Registry enrollment to under‐served groups through an outreach strategy designed to overcome barriers of communication and trust. To date there have been over 60 outreach events across the state. Current enrollment stands at 4228 enrollees, of whom 34% are self‐identified as minority group members (30.5% African American) and 2.8% identified as Hispanic. As the Registry begins assisting research studies with recruitment, we plan to develop methods to effectively reach individuals with and without easy digital accessConclusionsThe NC Registry for Brain Health is growing rapidly and has a diverse membership representative of the state population, demonstrating that groups often under‐represented in research studies have an interest in participating in research. Interfacing with under‐served communities, through outreach events and other face to face interactions, is crucial to ensure the community has access to trusted information when making decisions about potential research participation.
iPSC‐derived engineered cerebral organoids (enCORs) as in vitro models of tauopathy
Authors: Lovejoy Christopher E.J. , Alatza Argyro , Arber Charles , Bradshaw Teisha , Lashley Tammaryn , Hardy John , Wray Selina 
Published: December 2020

AbstractBackgroundFamilial Alzheimer’s disease (fAD) is caused by mutations in PSEN1, PSEN2 and APP. PSEN1 forms the catalytic core of g‐secretase, a membrane protease which cleaves numerous substrates including APP and Notch. We have previously shown that our panel of fAD patient‐derived iPSCs show altered APP processing and Ab generation. Here we investigated whether mutations led to altered Notch cleavage in neural precursors. We hypothesised that reduced Notch cleavage in fAD lines would promote premature differentiation during iPSC neuronal differentiation and during adult hippocampal neurogenesis.MethodWe generated 2D cortical neurons and 3D cerebral organoids from a panel of 14 donor‐derived iPSC lines (5 controls, 2 APP mutation lines and 7 PSEN1 mutation lines). Neurogenesis was quantified via the proportion of neural precursors versus the number of post‐mitotic neurons at timepoints of neural commitment. In addition, we quantified newly generated neurons in the post‐mortem hippocampus of 3 control brains and 7 brains derived from fAD mutation carriers.ResultWe describe a small, yet reproducible premature differentiation phenotype in lines containing mutations in PSEN1 during in vitro neurogenesis. This is, at least in part, due to reduced Notch signalling; which drives terminal differentiation. These findings are corroborated in independent orthogonal iPSC systems, namely 2D neurogenesis and 3D organoid differentiation. We see describe robust, quantifiable neurogenesis in post‐mortem tissue using b‐III‐tubulin immunohistochemistry. Results are suggestive of mutation‐specific effects and also a premature ageing phenotype in fAD tissue.ConclusionThese findings reveal insights into the functional outcomes of fAD mutations. Mutations in PSEN1, but not APP, alter Notch signalling in neural precursors, which in turn drives premature terminal differentiation. Premature differentiation and mutation‐specific differences both necessitate careful consideration for drug design and patient stratification.
Neuropsychological and biochemical features of cognitive resilient octogenarians and nonagenarians
Authors: Zegada Luis Fernando , Zegada Luis 
Published: December 2020

AbstractBackgroundAlzheimer’s dementia has evolved into a biological construct based on fluid and imaging biomarkers to aid in early diagnosis. Biomarkers are expensive and not widely available. It is therefore important to define signatures of cognitive resiliency to better identify this group in the prodromal stages of dementia. Our AIM was to determine neuropsychological and biochemical characteristics of cognitively intact patients older than age 80.MethodSingle center, cross‐sectional study involving forty patients older than 80, admitted to a community hospital. Participants with diagnoses of dementia, delirium, history of falls, dependency on cognitively focused IADL, and those residing in residential care were excluded. Recruited patients were subjected to neurocognitive evaluation, with emphasis on episodic/working memory, semantic cognition, and visuoperceptual/executive spheres, using the Rey‐Osterrieth figure copy/recall (ROSC) test. Regression analysis was used to establish correlation.ResultThe mean age was 85 years (SD 4.06). The mean level of education was 12.12 years (SD 2.93). Only 28% of participants lived alone. Semantic evaluation was the most difficult task, with only 48% of patients able to pass. Patients who answered 3 memory tasks right, had a mean score of 21 (SD 4.6) on the ROSC recall. Those who pass 2 memory tasks, had a mean score of 18.75 (SD 5.20) on the ROSC recall, and those who pass only one, or failed all of them, had a mean score of 9. We identified the ROSC recall as the most powerful predictor of cognitive resiliency. Age correlated well with ROSC recall (p 0.0017, CI 45‐126), but no years of education (p 0.21, CI 2.32‐21). Hemoglobin had a significant effect on ROSC copy (p 0.0019, CI 5‐26), but no ROSC recall (p 0.84, CI ‐14‐12). No correlation was found between ROSC recall and MCV, RDW, or albumin level.ConclusionWe corroborate that age is the single most important factor for cognitive decay, whereas a normal hemoglobin level appears to be protective. Level of education seems to lose its protective effect in the old‐old and oldest‐old population. Patients able to perform well on the three types of memory, showed great proficiency on the ROSC recall.
The PIONEER Study: A multi‐center, randomized, double‐blind, placebo‐controlled phase 2 trial of the effects of T3D‐959 on safety, cognition, function and plasma biomarkers in mild to moderate Alzheimer’s disease subjects: Rationale and study design
Authors: Didsbury John , Strittmatter Warren , Chamberlain Stan , Gabriel Hoda 
Published: December 2020

AbstractBackgroundDysfunctional glucose and lipid metabolism are key drivers underlying pathological pathways ultimately resulting in Alzheimer’s disease (AD). T3D‐959 is a small molecule, orally delivered, brain penetrating, novel PPAR delta agonist with 15‐fold lower PPAR gamma potency that acts to maintain homeostasis of glucose and lipid metabolism. Ubiquitous brain expression of PPAR‐delta, its critical role in regulating glucose and lipid metabolism and phenotype of PPAR‐delta null mice, coupled with a promising safety profile and multiple efficacy signals in an exploratory Phase 2a clinical trial (NCT02560753) in patients with mild‐to‐moderate AD, provide the foundation for the next Phase 2 clinical trial, the PIONEER Study [Prospective therapy to Inhibit and Overcome Alzheimer's Disease Neurodegeneration via Brain EnErgetics and Metabolism Restoration].MethodsPIONEER is a randomized, double‐blind, placebo‐controlled, Phase 2 trial involving 256 mild to moderate AD patients (MMSE=16‐26) dosed orally once‐a‐day for 24‐weeks in 4 parallel arms (T3D‐959 active arms of 15mg, 30mg and 45mg QD and a placebo arm in a 1:1:1:1 ratio). Co‐primary outcome measures include the ADAS‐cog11 cognition and global function CGIC measures. Secondary and exploratory outcome measures include change from baseline in plasma Aβ 42/40 ratio, NfL and tau between subjects treated with T3D‐959 compared to placebo, evaluation of the effect of T3D‐959 compared with placebo on apathy as measured by the NPI, on functional decline as measured with ADCS‐ADL, on executive function as measured using the DSCT, on verbal fluency, on plasma metabolomic and proteomic biomarkers and change in absolute regional, and whole brain, cerebral metabolic rate for glucose (CMRgl) as assayed by FDG‐PET.ResultsCognitive and functional endpoints, as well safety data will be presented and discussed.ConclusionsPIONEER is designed to evaluate the efficacy and safety of multiple dose strengths of T3D‐959 in patients with mild to moderate severity AD.
Group therapy for family caregivers of PWD at risk for complicated grief: A feasibility and efficacy analysis of pre‐loss group therapy
Authors: Supiano Katherine P , Andersen Troy C , Beynon Cynthia , Luptak Marilyn , Iacob Eli 
Published: December 2020

AbstractBackgroundOur previous evaluation of Complicated Grief Group Therapy (CGGT) in bereaved dementia family caregivers demonstrated efficacy and identified intervention elements suitable for adaption into a preventative care approach.MethodWe adapted CGGT treatment elements into a manualized 10 session pre‐loss group psychotherapy—Pre‐Loss Group Therapy (PLGT)—for dementia caregivers at risk for Complicated Grief (CG). We implemented and evaluated three PLGT cohorts in three long‐term care facilities with family caregivers at‐risk for CG whose care recipient had a life expectancy of 6 months or less and resided in a long‐term care facility (NT = 24).ResultEvaluation of participant preparedness for the death of the person with dementia (PWD), self‐care and grief outcomes showed significant improvement across domains between pre and post‐group. Notably, there was a statistically significant decrease in grief as measured by the Inventory of Complicated Grief score from baseline (M = 25.67, SE=1.80) to post‐group (M = 14.41, SE=1.65) t(21)= 6.280, p<0.001 and a statistically significant increase in meaning making as measured by the Grief and Meaning Reconstruction Inventory score from baseline (M = 111.74, SE=1.96) to post‐group (M = 116.46, SE=1.65) t(21)= ‐3.197, p<0.01. Clinician‐rated grief severity declined (N=22, β = –0.472, SE = 0.018, p < 0.001) per week and grief improvement increased (N=22, β = 0.259, SE = 0.023, p < 0.001) per week, as assessed on the Clinician Global Impressions Scale. We evaluated Early‐Stage intervention feasibility components of recruitment, retention, treatment fidelity, as well as PLGT participant acceptability, tolerability, satisfaction and treatment adherence. Of participants, 75% completed at least 80% of sessions, and 91% completed all assessments. Each feasibility target was achieved.ConclusionThis is the first known application of proven therapeutic strategies to address CG applied to high‐risk dementia caregivers prior to the death of the PWD. Caregivers at risk for CG may benefit from group therapy targeting preparedness and pre‐loss grief experience, as we provide with PLGT. PLGT holds promise for translation into comprehensive caregiver support programs and delivered to active caregivers of living PWD at risk for CG across community and in the settings of hospice and long‐term care.
Investigating predictive models for earlier diagnosis of cognitive impairment using multimodal eye biomarkers
Authors: DeBuc Delia Cabrera , Arthur Edmund , Feuer William , Persad Patrice , Somfai Gabor Mark , Kostic Maja , Oropesa Susel , Mendoza‐Santiesteban Carlos 
Published: December 2020

AbstractBackgroundThe purpose of this study is to investigate predictive models for earlier diagnosis of cognitive impairment (CI) using the eye.MethodProspective age‐matched subjects (n = 69, 55+ years) w/o CI and the presence of any ophthalmic history were recruited. The Montreal Cognitive Assessment scores, retinal images (EasyScan, iOptics) and full‐field electroretinogram (RETevalTM, LKC Technologies, Inc.) were obtained. The multifractal behavior in the skeletonized optic‐disc region was analyzed using the generalized dimensions (D0, D1 & D2) and singularity spectrum f(α) vs. α, both calculated with the ImageJ program. The lacunarity (Λ) was also calculated by measuring the gap dispersion inside each retinal image. Logistic regression was used to construct predictive models to discriminate between phenotypes obtained from individuals w/o CI. Independent variables were divided into sets (see Table 1). Then, five hierarchical set models were fitted with all independent variables forced in. For each model, predicted probabilities were used to construct Receiver Operating Characteristic (ROC) curves. In a separate analysis, all independent variables were allowed inclusion in a parsimonious forward stepwise fashion, and a ROC curve was also constructed with its model‐predicted probabilities. Efficacy of discrimination was summarized with the area under the ROC curve (AUROC) and Youden’s index.ResultOf the 69 participants, 32 had CI (46%). Figures 1 and Table 1 shows that the overall predictive accuracy of the model 5 in discriminating patients with CI from cognitive healthy subjects may be better (AUROC∼0.95) than that of the other combined measurements AUROC range∼[0.73 ‐ 0.88]. In the separated analysis with all independent variables, the singularity exponent a2 was the most significant predictor of CI. Once this was accounted for, none of the other parameters was statistically significant except Flicker IT. Therefore, a2 and Flicker IT were included in a single model to obtain a powerful predictive index: Xlinear = 18.387 + (0.736) × (Flicker IT)‐(26.887) x (a2) being the Predictive probability of CI = expXlinear/(1+expXlinear). The AUROC for this predictive model was 0.897 (SE = 0.050) and was highly significant (p < 0.001).ConclusionOur results showed that the predictive model using multimodal eye biomarkers has potential to target cognitive screening toward individuals at increased risk of CI.
Exposure to low output power laser with transcatheter intracerebral photobiomodulation therapy reduces mental and cognitive disorders and dementia in Alzheimer's disease
Authors: Maksimovich Ivan V. 
Published: December 2020

AbstractBackgroundTranscatheter Intracerebral Photobiomodulation Therapy (PBMT) using low output power laser is a promising area in AD treatment. The method is aimed at stimulating angiogenesis, restoring cerebral microcirculation, stimulating metabolic processes and ATP metabolism in neuronal mitochondria, stimulating neurogenesis and regenerating cerebral tissues.MethodThe treatment was performed for 93 patients suffering from various AD stages with dementia, cognitive and mental disorders aged 34‐80 (average age 67.5), men ‐ 32 (34.40%), women ‐ 61 (65.59%). The examination included: CDR determination, MMSE testing, CT, MRI with calculation of temporal lobe atrophy degree and determination of dementia stage using the Tomography Dementia Rating scale (TDR), cerebral scintigraphy (SG), rheoencephalography (REG), cerebral MUGA. Test Group: 48 (51.61%) patients underwent transcatheter intracerebral Photobiomodulation Therapy (PBMT) using a helium‐neon laser. According to atrophy and dementia degree, cognitive and mental disorders severity, the patients were divided: preclinical AD stage (TDR‐0) ‐ 4 (8.33%); early AD stage (TDR‐1) ‐ 16 (33.33%); medium AD stage (TDR‐2) ‐ 21 (43.76%); severe AD stage (TDR‐3) ‐ 7 (14.58%) patients. Control Group: 45 (48.39%) patients underwent conservative treatment (Memantine 5‐20mg or Rivastigmine 3‐12 mg daily). According to atrophy degree, the severity of dementia, cognitive and mental disorders, the patients were divided: preclinical AD stage (TDR‐0) ‐ 6 (13.33%); early AD stage (TDR‐1) ‐ 13 (28.89%); medium AD stage (TDR‐2) ‐ 15 (33.34%); severe AD stage (TDR‐3) ‐ 11 (24.44%) patients.ResultAn early follow‐up period of 6‐12 months. Test Group: all 48 (100%) patients showed improvement in cerebral microcirculation and signs of cerebral temporal lobes volume increase, which indicates neurogenesis and cerebral regenerative changes. The process was accompanied by clinical condition improvement, dementia decline, cognitive and mental functions restoration. Control Group: during the treatment, there was no stable improvement in the patients’ condition but a tendency to further increase in cerebral involutive changes, which was accompanied by dementia growth, cognitive and mental impairment.ConclusionTranscatheter intracerebral PBMT is a promising, effective AD treatment. It diminishes dementia, cognitive and mental disorders, and allows improving the quality of patients’ life and restoring their daily activity.
Saccadic eye movements associated with executive function decline in mild cognitive impairment and Alzheimer’s disease
Authors: Pereira Marta Luisa Goncalves de Freitas , Villa Martina , Koh Do Hyong , Camargo Marina von Zuben de Arruda , Belan Ariella Fornachari , Radanovic Marcia , Pomplun Marc , Forlenza Orestes Vicente 
Published: December 2020

AbstractBackgroundAbnormalities in eye movement metrics have been related to cognitive decline in dementia (Garbutt et al., 2008; Crawford et al., 2005), however, little is known about its association with executive dysfunction prior to the onset of Alzheimer’s disease (AD). The objective of this study was to determine whether older adults with mild cognitive impairment (MCI) or incipient dementia due to AD display subtle signs of impairment in executive functioning as compared to healthy controls, through the analysis of eye movement behavior.Method93 elderly individuals were allocated into three groups according to cognitive status: normal controls (CTRL, n=28), mild cognitive impairment (n=44) and Alzheimer’s disease (n=21). All groups were tested with an eye tracking‐assisted protocol composed of a prosaccade (PS) and an anti‐saccade (AS) task. The PS task required a fast, automatic saccade towards a peripheral target stimulus. In the AS task (measure of executive functioning), subjects had to inhibit an prosaccade towards the target stimulus and initiate a voluntary saccade in the opposite direction.ResultThe PS task revealed a similar saccadic performance across the three groups. The AS task had a greater impact on the frequency and latency of eye movement metrics in each group, with AD subjects showing a greater executive decline than CTRL and with MCI group performing intermediately. MCI were similarly impaired as AD in their voluntary saccadic reaction times, with a longer time to correct erroneous saccades. Correlations revealed relationships between eye movement metrics in the AS and measures of inhibitory control, attention, working memory and self‐monitoring.ConclusionThe three groups showed a similar pattern of eye movements in the PS task, with both patients groups revealing a preserved automatic saccadic control compatible with the pattern observed in healthy ageing. AS task confirmed that cognitive impairment in the MCI‐AD continuum affects eye movement patterns reflecting executive deficits in inhibitory control, working memory and executive‐attention control subjacent to voluntary saccades. MCI revealed an intermediary impairment in these executive domains, as compared to AD (highest impairment) and CTRL. However, they showed significant increased response times similar to AD subjects, in order to overcome these deficits.
Behavior and amyloid profiles modify the association of tauopathy/neurodegeneration and cognitive decline in Alzheimer’s disease
Authors: Ge Xinting , Qiao Yuchuan , Zhang Jiong , Shi Yonggang 
Published: December 2020

AbstractBackgroundTau tangles and amyloid plaques are specific biomarkers that define dementia of Alzheimer’s disease (AD). However, behavioral changes or neuropsychiatric symptoms (NPS) are the natural course of AD, which impact the patients’ quality of life and caregivers’ burdens. Relationship between tau tangles or changes of cortical thickness and ‘noncognitive’ symptoms such as behavioral changes were understudied.Method497 subjects were selected from Alzheimer’s Disease Neuroimaging Initiative (ADNI) project. Participants underwent tau positron emission tomographic (PET) scanning with 18F AV‐1451, Aβ PET scanning with florbetapir or florbetaben, magnetic resonance imaging, and cognitive and behavioral testing. A 4‐group division approach was proposed using both amyloid (A‐/A+) and behavior (B‐/B+) status: A‐B‐, A‐B+, A+B‐ and A+B+. Multivariable linear regression model was used to delineate the relationship of tauopathy/neurodegeneration and cognitive decline for each group.ResultThe tau deposition increased significantly from the A‐ group to the A+ group, and the associated regions spread into nearly the whole brain. No correlations of the cortical thickness with cognitive decline were found for both the A‐ and A+ groups. Considering the behavior status, no associations were found for both the A‐B‐ group and the A+B‐ group. The association of cognitive decline with tau deposition was observed in the temporal lobe (entorhinal cortex, para‐hippocampal gyrus, et., al) for the A‐B+ group and spread into nearly the whole cerebrum for the A+B+ group. For cortical thickness, the associations with cognitive decline show similar spreading patterns of tau deposition for the A‐B+ group while nearly no difference of the associated regions for the A+B+ group.ConclusionThe association of cognitive decline with tauopathy/neurodegeneration were driven by the subjects with abnormal behavior status (B+ groups), while there were nearly no associations for B‐ groups (A‐ and A+). NPS may have the ability to improve the differentiation sensitivity of Aβ on the severity of tauopathy/neurodegeneration. Several factors such as tau tangles, amyloid plaques, cortical atrophy, and behavior symptoms should be considered together for neuropsychiatric disorder diagnosis.