bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of NPTX2 as a prognostic biomarker of Alzheimer’s disease through a longitudinal CSF proteomics study in ADNI subjects
Authors: Libiger Ondrej , Shaw Leslie M , Watson Mark , Nairn Angus C , Umaña Kelly , Canet‐Avilés Rosa M , Jack Clifford R , Breton Yannick‐André , Cortes Laetitia , Chelsky Daniel , Spellman Daniel S , Baker Susan , Raghavan Nandini , Potter William 
Published: December 2020

AbstractBackgroundMany biomarkers have been identified which are relevant to studies of Alzheimer’s disease (AD), especially pertaining to the evolution of amyloid plaque, tau tangle pathology and loss of brain tissue. There remains, however, the need for additional biomarkers that reflect pathologic processes affecting neuronal function during pre‐clinical and prodromal stages, to help accelerate drug development efforts.MethodA retrospective investigation of longitudinal changes in concentrations of five analytes (CgA, NPTX2, VGF, SCG2, FABP3) was performed in CSF of ADNI subjects. Rates of longitudinal change in these candidate proteins were compared between: a) Cognitively normal subjects (CN; n = 76) versus subjects with mild cognitive impairment (MCI; n = 111) at baseline; b) Subjects categorized as p‐Tau181/Aβ1‐42 ratio positive versus negative at baseline; and c) ‘Progressors’, i.e., subjects who progressed from CN to MCI or MCI to Dementia within a predefined period versus subjects categorized as ‘non‐progressors’. Following a pre‐specified analysis plan involving mixed‐effects linear models adjusting for relevant covariates, the association between changes in each analyte’s concentration and subjects’ clinical progression was quantified.ResultNPTX2, a protein involved in synaptic function, showed the strongest association with baseline clinical diagnosis of MCI, and a positive p‐Tau181/Aβ1‐42 ratio – the biomarker profile indicative of AD. Differences in the rates of decline in NPTX2 concentration between subjects classified as CN and MCI as well as between p‐Tau181/Aβ1‐42 ratio positive and negative subjects were highly significant (p=0.008 and p<0.0001 resp.), suggesting a complex interaction between the rate of decline in subjects at various stages along the disease continuum. Of the five analytes, only the rates of change in NPTX2 concentrations differed between progressors and non‐progressors (mean difference: 0.08 ± 0.02 ng/mL/year); p = 0.0004), further validating the association of changes in NPTX2 concentration and clinical prognosis. Additional exploratory analyses indicated the presence of a correlation between NPTX2 rates of change and declining cognition measured by MMSE (coef. = 0.3, p = 0.02), and Adas‐Cog 13 (coef. = ‐0.3, p = 0.01).ConclusionThese results suggest that NPTX2 concentration may serve as a prognostic biomarker of accelerated cognitive decline in at least a subset of individuals with AD.
A systematic review of neuroimaging findings in subjective cognitive decline
Authors: Parker Ashleigh F , Ohlhauser Lisa , Scarapicchia Vanessa , Smart Colette M , Gawryluk Jodie 
Published: December 2020

AbstractBackgroundIndividuals with subjective cognitive decline (SCD), who self‐report changes in cognition, but are within the normal range on neuropsychological testing, are thought to be the earliest along the cognitive continuum between healthy aging and Alzheimer’s disease (Jessen et al., 2014). This study aimed to synthesize findings of neuroimaging studies using various modalities to investigate changes in the brain in those with SCD.MethodPubMed and PsycINFO databases were searched for neuroimaging studies of individuals with SCD. Quality assessment was completed using the Appraisal tool for Cross‐Sectional Studies (Downes, Brennan, Williams, & Dean, 2016).ResultIn total, 108 neuroimaging studies investigating SCD samples were identified. Specifically, 45 studies used MRI, 8 used EEG, 5 used MEG, 3 used CT, 26 used PET, 2 used SPECT, and 19 studies used multi‐modal neuroimaging methods. Many studies investigated differences between healthy controls and those with SCD. Across imaging modalities, findings revealed significant differences in brain structure and function between these groups.ConclusionIt is valuable to synthesize the results of studies found in this area to identify neuroimaging biomarkers present in those with SCD. Identifying changes in the brain using objective and physiologically based measures at this early clinical stage will help to characterize the progression of Alzheimer’s disease. In future neuroimaging investigations of SCD, it would be useful for studies to include larger sample sizes, examine groups longitudinally, and use multi‐modal neuroimaging methods. Incorporating these components in future studies could provide a better understanding of changes in the brain that are associated with subsequent conversion to mild cognitive impairment or Alzheimer’s disease.
Inhibition of peripheral VEGF signaling rapidly reduces leucocyte obstructions in brain capillaries and improves cortical blood flow in an Alzheimer’s disease mouse model
Authors: Ali Muhammad , Falkenhain Kaja , Haft‐Javaherian Mohammad , Murtaza‐Ali Muhammad , Njiru Brendah N , Nishimura Nozomi , Schaffer Chris B , Bracko Oliver 
Published: December 2020

AbstractBackgroundWe recently found that increased obstructions in capillaries caused by adhesion of leucocytes in the cortical microvascular leads to a ∼20% reduction of cerebral blood flow (CBF) in mouse models of Alzheimer’s disease. Here, we explore the contribution of peripheral Vascular Endothelial Growth Factor (VEGF) signaling at the luminal side of the brain microvasculature as a driver of capillary stalling and blood‐brain barrier (BBB) integrity in the APP/PS1 mouse model of AD.MethodThe number of stalled cortical capillaries and blood flow speeds were measured in cortical capillaries using high resolution in vivo two‐photon imaging, before and after one hour and two weeks of i.p. anti‐VEGF164 antibody injection. Capillary stalls were measured using the citizen science platform Stall Catchers. The blood‐brain barrier integrity was analyzed using immunohistochemistry.ResultWe found that inhibition of VEGF signaling in APP/PS1 mice reduces capillary stalling by ∼75% and improves average capillary speed by ∼50%. In contrast, no such effects were seen in wild‐type saline‐injected controls. The anti‐VEGF164 injection also reduced overall eNOS protein concentrations and increased the tight junction protein levels of occludin. Intriguingly, the few APP/PS1 capillaries that were still prone to obstructions after anti‐VEGF treatment had lower occludin concentrations between their endothelial cells than flowing capillaries. We further demonstrate that capillary stalling reductions and capillary speed improvements occur within an hour of intraperitoneal anti‐mouseVEGF164 injection. At the same time scale, anti‐VEGF treatment reduced Evan’s blue diffusion across the BBB.ConclusionThis data demonstrates that peripheral inhibition of VEGF‐signaling in APP/PS1 mice restores aberrant eNOS/occludin‐associated BBB permeability, and is associated with decreased capillary stalls and increased CBF.
Chronic head injury promotes tau and amyloid‐beta pathology and accelerates cognitive decline in a humanized knock‐in model of Alzheimer's disease
Authors: Chiasseu Marius , Fesharaki Arman , Saito Takashi , Saido Takaomi C , Strittmatter Stephen M 
Published: December 2020

AbstractBackgroundClinical manifestation of Alzheimer's disease (AD) symptoms is known to reflect interactions between environmental and genetic factors. Unfortunately, preclinical modeling of AD has been relying primarily on transgenic overexpression of rare dominant mutations, with little considerations to the role the environment might play in triggering the disease. Hence the disappointing results towards translational progress in disease modifying therapies. Mild traumatic brain injury (mTBI) is a well‐known environmental risk factor for dementia, including Alzheimer’s, yet there has been limited mechanistic analysis of mTBI contribution to AD pathology. Here, we investigate the interplay between mTBI and Aβ precursor protein (APP) gene mutation in AD pathogenesis.MethodWe employed a knock‐in (KI) model of AD that expresses the Aß‐containing exons from human APP bearing the Swedish and Iberian (AppNL‐F/NL‐F
) mutations that we subjected to repeated mTBI (rmTBI). Injury was induced in anesthetized 4‐month‐old mice by stereotactically applying daily, a mild mechanical force on the head using a controlled cortical impactor. Impacts were applied at a speed of 5 m/s, a duration of 100 ms, and depth of 1 mm for a total of 14 days alternating between each side of the cranium. Anesthetized, uninjured genotype‐ and age‐matched mice were used as sham controls. At 3‐ and 8‐months post‐injury, cortical Aβ, phospho‐tau and Iba1 expression as well as cognitive status were assessed in the injured KI subjects.ResultOur data reveal that relative to controls, rmTBI enhances accumulation of amyloid‐β and hyperphosphorylated tau inclusions, as well as neuroinflammation in KI mice, this in areas both proximal and distal to the injury site. Furthermore, novel object recognition and Morris water maze tests demonstrated that the AppNL‐F/NL‐F
mutations synergistically exacerbates the cognitive deficits triggered by rmTBI.ConclusionTherefore, this study demonstrates that combining genetic and environmental factors provides a more robust approach for modelling AD, and that chronic head injury substantially accelerates Alzheimer's pathology in a genetically susceptible situation.
Alzheimer’s pathologic change indexed by CSF B‐amyloid42 associates with longitudinal alterations in myelin content
Authors: Yang Kao Lee , Dean Douglas C , Oh Jennifer M , Koscik Rebecca L , Ma Yue , Kohli Akshay , Chin Nathaniel A , Carlsson Cynthia M , Johnson Sterling C , Asthana Sanjay , Zetterberg Henrik , Blennow Kaj , Alexander Andrew L , Bendlin Barbara B 
Published: December 2020

AbstractBackgroundCSF Ab42 levels are associated with myelin content alterations in cognitively‐unimpaired adults (Dean et al, 2017), suggesting that myelin alterations may be an early feature of the Alzheimer’s disease (AD) pathophysiological cascade. We expand on these prior findings to examine longitudinal change in myelin content.Method98 cognitively‐unimpaired (Table 1) participants from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention underwent longitudinal multicomponent relaxometry (mcDESPOT) MRI, T2FLAIR MRI, and lumbar puncture (LP). All mcDESPOT MRI were normalized to MNI space using ANTs. White matter lesion volumes were extracted from T2FLAIR images using Lesion Segmentation Toolbox version 2.0.1 in SPM12. CSF was assayed for Ab42 using enzyme‐linked immunosorbent (INNOTEST) methods. 212 mcDESPOT‐derived myelin water fraction (MWF) maps, sensitive to myelin content, were generated for this analysis. MWF values were extracted from 6 white matter tracts affected in AD, and MWF values were averaged across regions to create a global index of myelin content at each timepoint. Linear mixed models were fit with longitudinal regional or global MWF as the outcome. All models included random intercepts and age‐related slopes with fixed effects of age (mean‐centered), sex, years between MRI and LP, white matter hyperintensity volume (log‐transformed) measured at first MRI, CSF Ab42 (mean‐centered) levels measured near first MRI, and Age*Ab42. All models were fitted in R (“lmer” package) version 3.6.0 and considered significant at unadjusted p < .05.ResultWe observed widespread age associations with myelin content such that older age associated with lower global myelin content (Figure 1) and lower CSF Ab42 was associated with lower global myelin content (Figure 2). There was no significant interaction of age and CSF Ab42 on global myelin content. However, an age*Ab42 effect in the cingulum and uncinate fasciculus indicated that older age and lower CSF Ab42 was associated with decreased myelin content (Figure 3).ConclusionWe previously found that lower CSF Ab42 was associated with lower myelin content among cognitively unimpaired adults. Here, we determined that for cognitively unimpaired middle‐aged adults, amyloid‐related longitudinal changes in myelin content also occur. Future studies will test if amyloid‐related myelin alterations may account for AD cognitive decline.
The Cognitive Behavioral Score Questionnaire (Q‐CBS) in phenotyping minor and major neurocognitive disorder syndromes
Authors: Sykara Konstantina , Ramirez Jeronimo Martin , Andronas Nikolaos , Mavragani Evdoxia , Tsekou Hara , Mougias Michalis , Karageorgiou Klimentini E , Karageorgiou Elissaios 
Published: December 2020

AbstractBackgroundThe demand for specialized care in neurocognitive disorders greatly surpasses its availability. Patients have complex needs and specialists are scarce. As a result, there is a gap between the needs of patients and the capacity of health systems to address them. Expert systems help fill this gap working towards early and accurate phenotyping (description) of neurocognitive disorders to better identify and successfully allocate the limited resources. We developed the Cognitive Behavioral Score (CBS), a 51‐item structured self‐administered questionnaire and its caregiver counterpart (cCBS), conducting exploratory analyses on clinical feasibility and diagnostic utility, as well as association to neuropsychological performance.MethodWe enrolled 29 patients (age: 71.5±11.7; education: 9.6±2.8 years) with minor or major neurocognitive disorder (late age‐of‐onset Alzheimer’s disease with various degrees of vascular comorbidity; MMSE= 26.0±4.3) through the Sleep & Memory Center of the Neurological Institute of Athens. CBS and cCBS were completed by patients and/or their caregivers, covering cognitive, behavior, autonomic, and sleep symptom severity and duration. Patients underwent physical examinations, neuropsychological, biochemical and imaging testing. Statistical analyses were conducted using Pearson ρ or Kendall τ as appropriate, depending on data deviation from normality.ResultsBoth CBS and cCBS were completed in‐clinic or at home within 5 minutes and provided a clinical overview of symptom progression. CBS and cCBS congruence total score was 0.36, certain domain‐specific sub scores were even better (0.46 – 0.67). Correlation to MMSE was better for cCBS (‐0.30), a feature reflective of the patient population. CBS and cCBS sub scores had varying degrees of correlation to domain‐specific neuropsychological tests, with historic symptoms of anomia having most and highest associations (≤ ‐0.76). Non‐cognitive symptoms were correlated to executive function, hinting to possible comorbid synucleinopathies or sleep deprivation.ConclusionThe study results suggest that both CBS and cCBS have diagnostic utility for the clinician. They allow faster and more accurate description and identification of syndromic neurocognitive disorders. With better understanding, resources can be allocated in a more directed and better‐planned manner, helping low resource settings. Also these questionnaires minimize the time in history taking, allowing health professionals to dedicate more time to the patients for better and individualized care.
Perspectives surrounding brain donation among African American research participants in the Northwestern University Alzheimer’s Disease Center
Authors: Dyslin Deborah Nicole , Dunlop Sara Rose , Aldridge Brenda , Tillotson Robin , Morhardt Darby 
Published: December 2020

AbstractBackgroundAlzheimer’s and related dementias (ADRD) disproportionately affect the African American community. Increased participation of African Americans in research is essential to further understand factors related to risk and resilience to ADRD. Brain donation remains the only mechanism to confirm a diagnosis of neurodegenerative disorders and is less common among African American research participants compared to White research participants across the US. Previous studies identified knowledge of brain donation, religious and or funeral plans, family support of decision, and distrust of medical/research community as important factors in African American participation in brain donation. However, perspectives of African American participants within the Mesulam Center ADRC are unknown.MethodsSeven focus groups, stratified by both cognitive and decision status were conducted as part of this analysis. Focus groups ranged in attendance from 2‐8 participants, plus 2‐4 study personnel. 34 research participants and/or study partners participated in this project. Focus groups were co‐facilitated by Northwestern social workers, a Northwestern neuroscience PhD student, and a social work intern at the regional senior center. All focus group discussions were audio recorded, subsequently de‐identified, transcribed and coded for emerging themes.ResultQualitative analysis revealed several themes: personal connection to memory loss or dementia; altruism; personal decision making, spirituality/religion; historical and current trauma related to healthcare and research; trust; representation of African Americans in clinical and research settings, and understanding the purpose and process of brain donation. Participant identified next steps include community education initiatives centered around brain donation, building trust between the community and research institutions, and increased community engagement by Northwestern in diverse communities.ConclusionOverall, our findings are consistent with previous findings. Themes highlight the issue of trust, importance of increased representation of African Americans among staff in aiding participation, lack of understand of the purpose and value of brain donation, and the need for purposeful acknowledgement of past traumas by the medical research community. Next steps include both community level and institutional interventions to aid in increased participation in brain donation among African American research participants.
Lower MRI‐indexed locus coeruleus integrity in autosomal‐dominant Alzheimer's disease
Authors: Dahl Martin J , Mather Mara , Werkle‐Bergner Markus , Kennedy Brianna L , Qiao Yuchuan , Shi Yonggang , Ringman John M 
Published: December 2020

AbstractBackgroundTau pathology, a hallmark of Alzheimer’s disease, accumulates early in life in the locus coeruleus, the primary source of cortical norepinephrine. Dysfunctions in the noradrenergic system are hypothesized to contribute to Alzheimer’s progression; however, in‐vivo evidence has been impeded by methodological challenges in non‐invasive assessments. Advances in high‐resolution brainstem magnetic resonance imaging (MRI) hold potential to investigate the association of locus coeruleus integrity and Alzheimer’s‐related neuropathological markers in vivo.MethodEighteen participants (34.7±10.1 years; 9♀) with or known to be at‐risk for mutations in genes associated with autosomal‐dominant Alzheimer’s disease (ADAD) were investigated. Genotyping confirmed mutations in seven participants (PSEN1, n = 6; APP, n = 1), of which four were symptomatic. Participants underwent 3T‐MRI, flortaucipir positron emission tomography (PET), and cognitive testing. Locus coeruleus MRI intensity, a non‐invasive proxy for neuronal density, was semi‐automatically extracted from high‐resolution brainstem scans. Locus coeruleus ratios—that is, a ratio of peak locus coeruleus intensity standardized to a pontine reference—were computed across the rostrocaudal extent of the nucleus. Standard uptake value ratios (SUVR) were calculated from partial volume corrected flortaucipir PET data using cerebellar gray matter as reference. SUVR images were mapped to the cortical surface which was parcellated into 36 regions of interest. Associations between locus coeruleus ratios, clinical variables, cognitive status, and tau burden were evaluated using non‐parametric Mann‐Whitney U‐tests and bootstrapped Spearman’s correlations.ResultRelative to healthy controls, symptomatic participants showed lower locus coeruleus ratios (Z = 2.177; p = 0.03). This effect was pronounced in rostral segments of the nucleus (Z = 3.077; p = 0.002) that project to the hippocampus. Among carriers of ADAD‐causing mutations, closer proximity to the mutation‐specific median age of dementia diagnosis was associated with lower locus coeruleus ratios (rho = ‐0.727; p = 0.048). Higher locus coeruleus ratios were observed in participants with unimpaired cognitive performance (rho = 0.527; p = 0.022). Tau burden, especially in occipito‐temporo‐parietal regions, was related to lower locus coeruleus ratios (rho = 0.54, p = 0.036).ConclusionOur finding of diminished locus coeruleus integrity in autosomal‐dominant Alzheimer’s disease suggest a role of the noradrenergic system in this neurodegenerative disease.
Choral singing with dementia: Examining the experience and impact of embodied and relational musical performance
Authors: Smith Andre P , Erb Tara , Kampen Ruth , MacDonald Stuart , Sheets Debra J 
Published: December 2020

AbstractBackgroundPromising research points to the potential of singing as a novel intervention to improve cognitive function and reduce levels of stress, anxiety, loneliness, and depression in persons with dementia (PwD) (Elliott and Gardner, 2018; Unadkat et al., 2016). This study explores the impact of participation in Voices in Motion (ViM), an intergenerational community choir program designed to engage and support persons with dementia (PwD), their care partners, and students in Victoria, British Columbia, Canada. Combining narrative interviews, focus groups and observations, the study examined care partners and PwD’s experiences of ViM and their views of the benefits of choir involvement and considered the impact of ViM on social inclusion and social relationships.MethodOver an 18‐month period, the study initiated and followed two ViM choirs—one active in research for three 3‐month sessions and the other for two sessions of the same time length. Data came from interviews with 23 dyads of PwD and care partners and focus groups with 29 high school students across the two ViM choirs. The interviews and focus groups were conducted at the end of each choir season over the course of the study.ResultThe thematic analysis revealed that PwD maintained an embodied ability to learn, experience, and perform songs in the choir despite considerable deficits in cognition, language, and memory. Results indicate that choral participation, as a type of embodied activity, effectively engages PwD and allows them to meaningfully express themselves as both singers and human beings. The ViM choirs facilitated the emergence of strong social relationships between PwD and care partners with the students who reported gaining a deeper and sympathetic understanding of PwD as individuals with rich life stories. Choral singing also served as an inspiring avenue for PwD to develop a strong sense of self and identity as choristers and performers.ConclusionViM facilitates the re‐humanization of dementia through well‐attended concerts and performances at public events while also challenging social narratives of decline which remain prevalent in society and stigmatize individuals living with dementia.