bluuebunny/crossref_metadata_2025_split huggingface dataset:
The relationship between flutriciclamide PET uptake and grey matter atrophy in mild cognitive impairment and Alzheimer’s disease
Authors: Raza Sanara , Calsolaro Valeria , Buckley Christopher , Gentleman Steve , Brooks David J. , Edison Paul 
Published: February 2022

AbstractBackgroundMicroglial activation plays a significant role in neuroinflammation in the neurodegenerative process. Microglial activation is characterised by the over‐expression of a mitochondrial protein (TSPO), that can be targeted by PET Tracers. This study aims to evaluate the relationship between [18F]GE180 PET uptake and grey matter atrophy.MethodIn this PET study, we evaluated microglial activation in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) using the novel TSPO ligand flutriciclamide ([18F]GE180). Forty‐eight participants have been assesed with [18F]GE180 PET using arterial input. Spectral analysis was used to generate parametric maps of the impulse response function at 90 minutes. Additionally, hippocampal volume analysis was performed on structural magnetic resonance images (MRIs).ResultIn a group‐wise analysis a significant reduction in hippocampal volume was found between the AD and healthy controls cohorts. Hippocampal volume significantly negatively correlated with the IRF90 in the temporal lobe and occipital lobes as well as and composite region in AD patients compared to healthy controls.ConclusionIn this [18F]GE180 PET imaging study in AD/MCI cohort, we have demonstrated that there is hippocampal atrophy when [18F]GE180 PET goes up in AD patients. The results indicate that regional [18F]GE180 PET uptake has a close association with neurodegeneration of key memories processing centre.
Tau pathology progression across PET‐based stages of regional amyloid deposition
Authors: Moscoso Alexis , Grothe Michel J. , Schöll Michael 
Published: February 2022

AbstractBackgroundPrevious research has consistently reported widespread tau aggregation in the presence of global amyloid‐β (Aβ) pathology, but the association of Aβ pathology severity with tau accumulation remains unclear. Here, we studied cross‐sectional and longitudinal tau aggregation in relation to progressive stages of regional Aβ deposition as determined by a recently established Aβ PET‐based staging approach.MethodWe examined 244 cognitively unimpaired (CU) and 180 impaired (CI) subjects from the Alzheimer’s Disease Neuroimaging Initiative with concurrent T1 MRI, 18F‐Florbetapir‐PET (FBP), and 18F‐Flortaucipir‐PET (FTP) scans. A subset of 153 individuals had at least one follow‐up FTP scan. An Aβ PET‐based staging method for FBP was used to stratify participants into four progressive stages of Aβ deposition. Linear regressions adjusted for age and sex were used to assess regional FTP uptake across Aβ stages in CU and CI individuals (additionally controlled for clinical diagnosis ‐ MCI/AD). Longitudinal tau accumulation was assessed in the pooled CU and CI sample, using linear mixed effects models adjusted for age, sex, and clinical diagnosis. Finally, we assessed cross‐sectional tau‐related markers (p‐tau181 and p‐tau181/Aβ1‐42) in cerebrospinal fluid (CSF) across Aβ stages in another subset of participants (n=227).ResultCross‐sectionally, FTP uptake in Braak I/II regions increased gradually from Aβ stages 1 through 4, though only Aβ stage 4 in CU and stages 3 and 4 in CI yielded widespread neocortical tau deposition compared to stage 0 (Fig. 1). Similarly, faster longitudinal FTP increases in Braak I/II regions were observed from Aβ stage 2 onwards, but only Aβ stages 3 and 4 showed faster tau accumulation in regions exceeding Braak I/II (Fig. 2). Corroborating the PET findings, cross‐sectional levels of p‐tau181 and p‐tau181/Aβ1‐42 in CSF showed gradual increases across Aβ stages 2‐4 (Fig. 3).ConclusionEarly stages of Aβ pathology selectively affect medial temporal lobe tau deposition, but more severe and widespread tau pathology does not occur before more advanced stages of Aβ deposition. Since these only cover a subpopulation of Aβ‐positive individuals as conventionally defined, specifically recruiting individuals at advanced Aβ stages might represent an effective strategy for clinical trials in which longitudinal tau PET is used as an outcome measure.
Correlates of neuroimaging measures with pathological scales of cerebrovascular disease
Authors: Vemuri Prashanthi , Kouri Naomi , Przybelski Scott A. , Labuzan Sydney A. , Lesnick Timothy G. , Reid Robert I. , Reichard Ross R. , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Mielke Michelle M. , Dickson Dennis W. , Graff‐Radford Jonathan , Murray Melissa E. 
Published: February 2022

AbstractBackgroundSummarizing the multiplicity and heterogeneity of cerebrovascular disease (CVD) features into a single measure has been difficult in both pathology and imaging studies. The objective of this work was to evaluate the association between neuroimaging surrogates of CVD and two available neuropathologic CVD scales in those with both antemortem imaging CVD measures and post‐mortem CVD evaluation. We used (1) Strozyk scale (Strozyk et. al. NBA 2010) which is based on presence and number of three macroscopic lesions (large infarctions, lacunar infarctions, and leukoencephalopathy) and (2) Kalaria scale (Deramecourt et. al. Neurology 2012) which summarizes detailed evaluation of vessel wall modifications (arteriolosclerosis, amyloid angiopathy), perivascular spaces, myelin loss, microinfarctions, and large infarctions.MethodWe identified n=51 individuals in Mayo Clinic Study of Aging (mean age of 83.8 years, 37% female) with MRI scans within 5 years of death. We computed CVD measures from DTI (fractional anisotropy of the genu of the corpus callosum [FAGCC] and fractional anisotropy of cingulum adjoining the hippocampus [FACGH]), FLAIR (white matter hyperintensities [WMH] and total number of infarctions), and T2* GRE (total number of microbleeds). We also computed our recently developed imaging CVD composite score which summarizes the variability in all individual CVD imaging measures described above. We computed the Strozyk and Kalaria scales on postmortem tissue. We used weighted linear regression models with adjustments for MRI scan time to death to evaluate the associations between the antemortem neuroimaging measures and pathology scales in those who had scans within 3 years of death (N=31) and 5 years of death (N=51) (tables 1 and 2).ResultOf all the neuroimaging measures, DTI measures were the best predictors of the Strozyk and Kalaria Scales (p<0.05). In sensitivity analyses of data in Table 1, FAGCC explained 44% and FACGH predicted only 5.5% variability in white matter sub‐component of the Strozyk scale. The CVD composite score was a poor surrogate of the composite pathological scales.ConclusionMicrostructural white matter injury measurement using DTI may be a good surrogate of pathological CVD scales and possibly captures diffuse (and early) changes to white matter and secondary neurodegeneration due to lesions.
Factors associated with disclosing a diagnosis of dementia to one’s social network: A systematic review
Authors: Kohl Gianna , Ulate Mauricio Molinari , Bhatt Jem , Scior Katrina , Charlesworth Georgina 
Published: February 2022

AbstractBackgroundDementia, to a certain degree in the early stages, can be a concealable condition. People with dementia often feel stigmatized and choose not to disclose their diagnosis to others. While concealing the diagnosis can prevent further stigmatization, it can also contribute to psychological consequences and limited social support, and prevent access to services and resources. The decision to disclose a concealable diagnosis is personal and complex, and a nuanced understanding of this decision is of great relevance to practitioners and researchers. This review examines factors influencing the decision to disclose or conceal a diagnosis of dementia to or from others, including individuals’ attitudes and experiences regarding disclosure or concealment.MethodThe protocol of this review has been registered on PROSPERO (CRD42020192495). A systematic literature search was conducted in the MEDLINE, PsycINFO, Embase, Emcare, CINAHL and Scopus databases. Search terms related to ‘disclosure’ or ‘concealment’, and ‘dementia’. Any research design was included and no date or language restrictions were applied. The methodological quality of included studies was assessed using the Mixed Methods Appraisal Tool (MMAT). Data was analyzed by means of thematic synthesis.ResultA total of sixteen studies published between 2000 and 2020 were included in the systematic review. Factors associated with disclosure and concealment were regrouped into codes and themes related to stigma, interpersonal relationships, personal identity, sense of control, privacy, symptom visibility, and advocacy and awareness. People with dementia may anticipate negative responses from others when they disclose their diagnosis to them, but reactions are often positive.ConclusionResults of this review suggest that the decision to disclose or conceal a diagnosis of dementia to or from one’s social network is highly individual and complex. People with dementia may often want to disclose, but do not know how. Raising awareness in the general public may support individuals in making optimal decisions about disclosure. Findings of this review will inform an empowerment intervention supporting disclosure decision‐making in people with dementia.
Differences in functional connectivity amongst older adults with mild cognitive impairment, subjective cognitive decline or normal cognition
Authors: Srikanthanathan Arunan , Vandermorris Susan , Verhoeff Nicolaas Paul L.G. , Chen Jean , Herrmann Nathan , Mah Linda 
Published: February 2022

AbstractBackgroundSubjective cognitive decline (SCD), hypothesized as a preclinical stage of Alzheimer’s disease (AD), describes individuals with subjective cognitive concerns despite normal performance on cognitive tests (Jessen et al., 2014). The reduced ability of the salience network (SN) to control switching between the central executive network (CEN) and the default mode network (DMN) has been linked to deterioration of cognitive functioning in normal aging, mild cognitive impairment (MCI) and AD dementia (He et al., 2014). Since alterations in functional connectivity between these networks have been implicated in MCI and AD, we compared connectivity of the SN with CEN and DMN amongst SCD, MCI and older adults who were cognitively unimpaired (CU). We predicted that SCD would show reduced SN connectivity between CEN and DMN networks compared to CU, but greater connectivity compared to MCI.MethodParticipants were 72 older adults [39 females, mean age=71.5] who were classified as either CU (n=26), SCD (n=29), or MCI (n=17). CU reported no memory concerns and performed within normal limits on neuropsychological (NP) assessments. SCD was established by affirmative responses to “Do you feel like your memory is becoming worse?” “If so, are you worried?” and normal NP test performance. MCI was based on the presence of subjective cognitive concerns and impairment on ≥ 2 NP measures within a cognitive domain, and functional independence. Participants underwent resting state functional magnetic resonance imaging (rs‐fMRI) for 6 minutes in an awake state with their eyes closed using gradient‐echo EPI BOLD at 3T (TR=2000ms, TE=30ms). Imaging data were processed using CONN toolbox. Seed‐based analysis using left and right frontoinsular cortices as seeds, which are key nodes in the SN network (MNI coordinates: ‐34,24‐,6 and 38,16,6, respectively), was conducted to measure connectivity between SN and the other two networks, CEN and DMN, within each group.ResultGroups did not differ in age, years of education, or sex distribution [F(2,69)=0.415, p=0.66;F(2,69)=2.20, p=0.12;X2(2, N=72)=1.89, p=0.39, respectively]. Results from imaging data analyses will be presented.ConclusionExamination of functional connectivity in SCD can be conducted using rs‐fMRI and may provide a window to the neurobiology of SCD.
"Let's Connect": Implementing a tablet‐based intervention for people with dementia and caregivers
Authors: Dove Erica , Shearer Teresa , Cotnam Karen , Gural Paul , Chamoun Elicia , Astell Arlene J 
Published: February 2022

AbstractBackgroundLet’s Connect training to use tablets and accessible apps with people living with dementia was implemented with staff, volunteers and family caregivers to evaluate the program impact.MethodEighty‐six staff and volunteers (18‐88 years of age) in 14 adult day programs and long‐term care homes in Ontario, Canada received training to deliver Let’s Connect groups as part of their daily or weekly programming. They were supported to deliver Let’s Connect group program for an initial eight sessions program with 118 people with dementia (56‐98 years of age). Staff and volunteers completed the Dementia Attitudes Scale (DAS) before and after the eight sessions and an exit interview, which was also completed by family caregivers who received training to support Let's Connect at home. People with dementia completed the QoL‐AD and SPS‐10 measure of social connectedness plus exit interviews.ResultThere was an improvement in staff and volunteer’s DAS score, while the people with dementia attending the adult day programs maintained their relatively high levels of social connectedness. Thematic analysis identified social interaction as a key benefit for staff, volunteers, caregivers and people with dementia. Further benefits and potential barriers were also identified.ConclusionLet’s Connect was well‐received, directly improved attitudes towards dementia and enhanced social activity. All of the sites that received training continued with the Let’s Connect group program after the research project ended. We will share our training strategy that can be applied to other tablet‐based activities.
Associations between biomarker status (amyloid, tau) and risk for progression to MCI/Dementia in the Harvard Aging Brain Study
Authors: Papp Kate V. , Rentz Dorene M. , Winskill Carolyn , Betensky Rebecca A. , Amariglio Rebecca E. , Schultz Aaron P. , Johnson Keith A. , Sperling Reisa A. 
Published: February 2022

AbstractBackgroundPrevious reports have shown that elevated AD biomarkers among clinically normal (CN) older adults confer heightened risk for a subsequent diagnosis of cognitive impairment using CSF and amyloid imaging. Here, we examine the impact of biomarker status on neuroimaging for both amyloid(A+/A‐) and tau(T+/T‐) on risk for clinical progression.MethodParticipants were CN at enrollment and underwent PET with 11CPiB to characterize global amyloid‐β(A) burden and F18Flortaucipir (FTP) to quantify inferior temporal tau(T). Participants were dichotomized as A+/A‐ and T+/T‐ using previously described mixture model distribution cut‐points. Because FTP only became available mid‐study, we undertook two analytical approaches: 1) cox regression analysis with first PiB scan as time origin (n=342, follow‐up=6.10 years;range=1‐9) with tau treated as a time‐varying covariate (setting it to T‐ prior to the first FTP scan if T‐ and setting it to missing prior to first scan if T+) and 2) first FTP scan as time origin with tau treated as fixed at that time (n=242, follow‐up=5.12 years;range=1‐7). Participants were diagnosed annually by biomarker‐blinded case conference. Covariates included Demographics and E4(+/‐).ResultIn the larger sample (31 individuals diagnosed with MCI/dementia), A+ was associated with increased diagnostic risk (HR=12.43, 95%CI=4.89‐31.57). In a model that included T as time‐varying (but not A), T+ was associated with increased risk for diagnosis (HR=4.46, 95% CI=0.99,20.11, p=0.051). Including A in the model, A+ was associated with increased diagnostic risk (HR=5.30, 95%CI=1.29,21.72) and T+ additionally appeared to confer higher risk, though not statistically significant (HR=2.89, 95%CI=0.12,67.73). An interaction term was not significant (HR for A+T+ versus A+T‐=4.65,95%CI=0.28,77.79). In the smaller sample with tau (19 individuals diagnosed), T+ was also associated with greater risk for diagnosis (HR=3.61, 95%CI=1.38‐9.40). Older age (HR=1.09, 95%CI=1.02‐1.18) and E4+ (HR=5.40, 95%CI=1.96‐14.89) were contributory. Both A+ (HR=13.83, 95%CI=2.82‐67.81) and T+ (HR=2.75, 95%CI=1.05‐7.24) are associated with higher diagnostic risk when included in the same model. A+T+ was associated with higher risk(HR=2.59, 95%CI=0.98‐6.83,p=0.055) compared with A+T‐.ConclusionA+ in combination with T+, is a significant risk factor for clinical progression. These findings provide further encouragement that interrupting A among CN older adults may mitigate risk for clinical progression.
Association of mitochondrial DNA copy number with brain MRI and cognitive function in the TOPMed Program
Authors: Zhang Yuankai , Liu Xue , Wiggins Kerri L. , Sofer Tamar , Guo Xiuqing , DeCarli Charles S. , Glahn David C. , González Hector M. , Levy Daniel , Nyquist Paul , Pitsillides Achilleas N. , Psaty Bruce M. , Rodrigue Amanda L. , Rotter Jerome I. , Smith Jennifer A. , Yanek Lisa R. , Seshadri Sudha , Bis Josh C. , Heckbert Susan , Fitzpatrick Annette L. , Fornage Myriam , Liu Chunyu , Satizabal Claudia L. 
Published: February 2022

AbstractBackgroundMitochondria are the main energy source for normal neuronal functions. Mitochondrial DNA (mtDNA) copy number (CN), a measure of mtDNA levels in the cell, correlates with cellular energy generating capacity and metabolic status. Previous studies have observed a significant decrease of circulating cell‐free mtDNA content in the cerebrospinal fluid of patients with Alzheimer's disease (AD). However, it is unknown whether mtDNA CN circulating in the blood is related to AD endophenotypes. We aimed to investigate the cross‐sectional association of mtDNA CN with MRI markers of abnormal brain aging and cognitive function.MethodWe included dementia‐free, multiethnic participants from seven population‐based cohorts with whole‐genome sequencing as part of the Trans‐Omics for Precision Medicine (TOPMed) program. The average mtDNA CN in whole blood was estimated as twice the ratio of the average coverage of mtDNA to the average coverage of the nuclear DNA using fastMitoCalc from mitoAnalyzer. Brain MRI markers included total brain volume, hippocampal volume, and white matter hyperintensities. General cognitive function was derived from at least three distinct cognitive domains using principal component analysis. We related mtDNA CN to AD endophenotypes assessed within 5 years of blood draw per cohort and further performed random‐effects or sample size‐weighted meta‐analyses. Models were adjusted for demographics and vascular risk factors.ResultHigher mtDNA CN was significantly associated with better general cognitive function (P‐values<0.05) in four cohorts after adjusting for age, sex, batch effect, self‐reported race/ethnicity, the time between blood draw and MRI/Cognitive evaluation, cohort‐specific variables, and education (Figure 1). Meta‐analysis across all cohorts confirmed and strengthened the significant association between mtDNA CN and general cognitive function (n=11,021, Beta=0.046, SE=0.01, P‐value=0.0002). Additional adjustment for diabetes, hypertension, hyperlipidemia, and obesity led to similar results (Beta=0.043, SE=0.01, P‐value=0.002). We observed no significant associations between mtDNA CN and brain MRI markers.ConclusionThis study suggests that higher mtDNA CN is cross‐sectionally associated with better general cognitive function in a large sample from diverse communities across the US, providing novel findings that support the role of mtDNA in healthy brain aging. Additional analyses are underway to relate mtDNA CN to AD endophenotypes prospectively and to incident dementia.
Associations between MRI‐assessed locus coeruleus integrity and restriction spectrum imaging of cortical gray matter microstructure
Authors: Elman Jeremy A. , Puckett Olivia K. , Hagler Donald J. , Pearce Rahul C. , Fennema‐Notestine Christine , Hatton Sean N. , Dale Anders M. , Panizzon Matthew S. , Lyons Michael J. , Franz Carol E. , Kremen William S. 
Published: February 2022

AbstractBackgroundThe locus coeruleus (LC) serves as the primary source of norepinephrine for the brain. Findings that the LC is one of the earliest sites of tau pathology make it a key structure in the early stages of Alzheimer’s disease (AD) progression. An important question is whether measures of LC integrity are associated with indexes of brain structure that may suggest broader patterns of neurodegeneration, particularly if such patterns are detectable prior to substantial macrostructural change. We therefore examined whether LC structural integrity was associated with differences in cortical gray matter microstructure among adults in early old age.MethodParticipants were 435 men (mean age=67.5; range=62‐71.7) from the Vietnam Era Twin Study of Aging (VETSA). Rostral LC structural integrity was indexed by contrast‐to‐noise ratio (LCCNR) from a neuromelanin‐sensitive MRI scan. Restriction spectrum imaging (RSI), an advanced multi‐shell diffusion technique, was used to characterize cortical microstructure, modeling diffusion in restricted, hindered, and free water compartments. Associations between LCCNR and isotropic diffusion within each compartment were examined for bilateral averages of 34 cortical ROIs defined by the Desikan‐Killiany parcellation. As a sensitivity analysis, we also examined whether LCCNR was associated with mean diffusivity (MD), a conventional diffusion tensor imaging (DTI) metric, or cortical thickness in the same regions.ResultAfter correction for multiple comparisons, higher LCCNR (greater structural integrity) was significantly associated with higher hindered isotropic diffusion and lower free water diffusion across multiple brain regions. In contrast, LCCNR was only associated with lower MD in one brain region and there were no associations with cortical thickness after correction.ConclusionThese results provide evidence that lower MRI‐assessed LC integrity is associated with patterns of cortical microstructure that may reflect a reduction in cellular membranes due to broader neurodegenerative processes. Individual differences in LC integrity were only detected with more advanced measures of microstructure that may be more sensitive to early changes than conventional diffusion imaging or macrostructural measures. These results highlight the potential utility for MRI of the LC and cortical microstructure in early identification of AD risk.