bluuebunny/crossref_metadata_2025_split huggingface dataset:
The evolution of neuropsychiatric symptoms in atypical variants of Alzheimer’s disease
Authors: Singleton Ellen H. , Rijkers Chrissy , Groot Colin , Papma Janne M. , Gillissen Freek , van Der Flier Wiesje , Scheltens Philip , Pijnenburg Yolande A.L. , Ossenkoppele Rik 
Published: December 2020

AbstractBackgroundNeuropsychiatric symptoms (NPS) constitute a pervasive component of Alzheimer’s disease (AD) for patients with a “typical” (i.e. amnestic‐predominant) phenotype. The prevalence and course of NPS is largely unknown in patients with atypical variants of AD and the few conducted studies are clouded by inclusion of Aβ‐negative individuals. Understanding the evolution of NPS in atypical AD is crucial for adequate patient care for individuals with these rare and early‐onset AD phenotypes.MethodsWe included 632 amyloid‐β‐positive subjects from the Amsterdam Dementia Cohort, including 26 behavioral variant AD (bvAD; showing ≥2/6 behavioral variant frontotemporal dementia (bvFTD) criteria), 30 logopenic variant primary progressive aphasia (lvPPA), 75 posterior cortical atrophy (PCA; Table 1). In addition, we included 47 AD patients with isolated predominant amnestic profiles (“amnestic AD”) and 454 amyloid‐β‐positive AD patients without predominant weaknesses on a single domain as “typical AD” reference groups. Linear mixed models were performed to compare baseline and longitudinal change in NPS as measured using Neuropsychiatric Inventory (NPI) scores across groups using general AD as the reference group (average follow‐up NPI assessment: 1.8 years).ResultAt baseline, apathy, appetite changes, disinhibition, aberrant motor behavior, and agitation were most frequent in bvAD patients, showing higher levels than typical AD (Figure 1). Apathy, irritability, anxiety, depression and appetite changes occured most frequently in PCA patients with similar levels as typical AD groups, whereas patients with lvPPA showed lower frequencies on 11/12 NPS compared to typical AD. Linear mixed models showed a significant decrease in total NPI score over time for the bvAD group (β(SE) = ‐0.0067 (0.003), p<.05). No significant changes were found in the other groups (all p>.05, Figure 2).ConclusionThis study assessing the baseline magnitude and longitudinal progression of NPS across amyloid‐positive clinical variants of AD suggests that patients with PCA do not show increased NPS, whereas patients with lvPPA show less NPS than typical AD patients. Despite high baseline levels of NPS in bvAD, NPS decrease over time, corresponding to observations in patients with bvFTD and suggestive of an inverted U‐shape trajectory of NPS in these patients.
A predictive, modeling‐based screening tool to enrich amyloid beta positivity in a cognitively normal sample
Authors: Truelove‐Hill Monica , Erus Guray , Pomponio Raymond , Bashyam Vishnu , Doshi Jimit , Habes Mohamad , Ezzati Ali , Bilgel Murat , Resnick Susan M. , Nasrallah Ilya M. , Wolk David A. , Davatzikos Christos ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundAs β‐amyloid (Aβ) targeted clinical trials have had questionable benefit in treating patients with early symptomatic Alzheimer’s disease, treatment would presumably be most effective if administered during the disease’s preclinical phase. PET scans, while highly sensitive to AD pathology, are less practical for screening a large, cognitively normal population for evidence of preclinical AD. Recruitment methods that produce an Aβ enriched sample before PET data collection would decrease participant burden and potentially lower costs. Here, we develop a simple predictive model using subject demographics, structural MRI, and APOE4 status. Using the model’s estimates of one’s probability of Aβ positivity, we significantly increase the proportion of Aβ+ subjects in a cognitively normal sample.MethodData from 875 participants from the Baltimore Longitudinal Study of Aging, Penn Memory Center and the Alzheimer’s Disease Neuroimaging Initiative database were separated into a discovery set including AD, MCI, and cognitively normal participants (n = 673) and a cognitively normal replication set (n = 202). Aβ prediction performance of a logistic regression model was compared across multiple predictor sets. Regression‐based probability values were used to threshold the data, i.e., participants whose values fell below a cutoff were excluded from the thresholded sample. The proportion of Aβ+ individuals between the restricted and complete samples was compared across multiple cutoffs.ResultApplying a probability cutoff of 0.4 yielded samples with significantly higher proportions of Aβ+ subjects in 3 of the 5 tested models (Table 1). The Lesions model achieved the highest sample enrichment; 40.54% of the thresholded sample were Aβ+, significantly higher than the base rate of 28.22%, χ2 (1) = 8.32, p = .004 (Figure 1). However, there were no significant differences between the enriched sample produced by the Lesions model and those produced by the other significant models, indicating sample enrichment is possible even with different predictors.ConclusionAβ+ probability metrics produced by predictive models provide a novel method of sample enrichment and can be used as an individualized measure of Aβ classification certainty. Fewer PET scans will be necessary to obtain a sufficient Aβ+ sample, reducing burden on participants and researchers and potentially lowering costs.
APOE4 impairs neuron‐astrocyte coupling of fatty acid metabolism
Authors: Qi Guoyuan , Mi Yashi , Shi Xiaojian , Gu Haiwei , Brinton Roberta Diaz , Yin Fei 
Published: December 2020

AbstractBackgroundAs the strongest genetic risk factor for late‐onset Alzheimer’s disease, the ε4 variant of apolipoprotein E (APOE4) is known to perturb both lipid homeostasis and energy metabolism in brain. However, the mechanistic role of APOE4 in modulating the bioenergetic aspects of lipid species, and its connection with cell‐type‐specific mitochondrial phenotypes are not well understood.MethodHere, in individual‐ and co‐culture models of primary neurons and astrocytes from humanized APOE3 or APOE4 knockin mice, we describe a loss‐of‐function role of APOE4 in regulating key mechanisms controlling neuron‐astrocyte coupling of lipid metabolism, from neuronal storage of fatty acids (FAs) in lipid droplets (LDs), to the mobilization of neuronal LDs and transport of FAs to astrocytes, and eventually to the energetic degradation of FAs in astrocytes.ResultCompared to APOE3, APOE4 decreases the sequestering of free fatty acids (FAs) in neuronal lipid droplets (LDs), elevates FA levels and leads to mitochondrial‐ and neuronal dysfunction. These neuronal LDs are eliminated upon astrocyte exposure and FAs are transported to astrocytes together with APOE, with APOE4 in either neurons or astrocytes diminishing the transport efficiency. In APOE4 astrocytes, increased mitochondrial fragmentation underlies a metabolic shift towards enhanced glucose metabolism and reduced FA β‐oxidation, which further elicits astrocytic LD accumulation. Moreover, the lesser capacity in eliminating neuronal lipids and performing β‐oxidation results in compromised ability of APOE4 astrocytes in providing metabolic‐ and synaptic support to neurons.ConclusionThese data support the coupling of neuron lipid homeostasis, astrocytic FA degradation with cell‐specific mitochondrial function, which is essential to protect neurons from bioenergetic deficits and lipotoxicity. Further, our findings reveal the mechanistic basis of APOE4 in disrupting inter‐cellular FA metabolism in brain that may underlie the exaggerated lipid dyshomeostasis and bioenergetic decline, and increased AD risk for APOE4 carriers.
Brainstem volumetric integrity in preclinical and prodromal Alzheimer’s disease
Authors: Dutt Shubir , Li Yanrong , Mather Mara , Nation Daniel A 
Published: December 2020

AbstractBackgroundAutopsy‐based neuropathological studies have suggested the tau pathology observed in Alzheimer’s disease (AD) originates in brainstem nuclei, but no studies to date have quantified brainstem volumes in clinical populations with biomarker‐confirmed mild cognitive impairment (MCI) or dementia due to AD or determined the value of brainstem volumetrics in predicting dementia risk. The present study examined whether MRI‐based brainstem sub‐structural volumes differ between cognitively normal (CN) older adults and those with MCI or dementia due to AD, and whether early preclinical brainstem volumes predict future progression to dementia.MethodAlzheimer’s Disease Neuroimaging Initiative participants diagnosed as CN (n=822), MCI (n=543), or AD (n=300) underwent baseline T1‐weighted structural MRI scanning with variable clinical follow‐up (6‐120 months). A subset of participants completed baseline fasting lumbar puncture to quantify levels of amyloid‐beta 1‐42 and phospho‐tau. We employed region‐of‐interest and voxel‐based morphometric methods to assess differences between clinically‐diagnosed and biomarker‐defined groups in volumes of the whole brainstem, midbrain, pons, and locus coeruleus. Longitudinal Cox regression analyses determined value of baseline brainstem sub‐structure volumes in predicting progression to a future clinical diagnosis of AD dementia.ResultCompared with CN individuals, we observed smaller regional volumes in whole brainstem, midbrain, pons, and locus coeruleus regions in patients clinically diagnosed with MCI and AD, and specifically within the midbrain in biomarker‐confirmed cases. Brainstem‐masked voxel‐wise comparisons confirmed volume reduction of a dorsal rostral brainstem region corresponding to the locus coeruleus in MCI and AD relative to CN, as well as in CN who progressed to AD dementia versus those that did not progress to AD dementia. In a preclinical risk analysis, cognitively normal individuals who later progressed to AD dementia exhibited smaller baseline midbrain volumes than individuals who did not develop dementia, and longitudinal analyses indicated smaller midbrain and locus coeruleus volumes conferred greater risk of progression.ConclusionOur study indicated that brainstem MRI changes are detectible in preclinical and prodromal populations. Our findings are consistent with the neuropathological observation that AD‐related pathology occurs early in brainstem nuclei and further suggest the clinical relevance of brainstem sub‐structural volumes for preclinical and prodromal AD populations.
Longer and more frequent naps predict incident Alzheimer’s dementia in community‐based older adults
Authors: Li Peng , Gao Lei , Gaba Arlen , Yu Lei , Yaffe Kristine , Buchman Aron S , Bennett David A , Hu Kun , Leng Yue 
Published: December 2020

AbstractBackgroundExcessive napping duration has been associated with cognitive decline. The effect of napping frequency is less understood, and little is known about the development of Alzheimer’s disease (AD) associated with napping. We tested whether longer or more frequent naps in the elderly are linked to the development of incident AD.MethodWe studied 1,180 older adults (age: 81.0±7.3 [SD]) in the Rush Memory and Aging Project who have been followed for up to 14 years. Motor activities (i.e., actigraphy; median length: 10 days; range: 2‐14 days) were recorded at baseline to assess napping characteristics objectively. We defined daytime napping episodes as motor activity segments between 10AM and 7PM with continuous zero‐activity for ≥10min but <1h (to avoid off‐wrist periods). Segments that were <5min apart were merged. Alzheimer’s dementia diagnosis was determined using the standard criteria (i.e., the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association). Cox proportional hazards models were performed to examine the associations of daily napping duration and frequency with incident AD.ResultOf 1,180 non‐demented participants at baseline (including 264 with mild cognitive impairment), 277 developed Alzheimer’s dementia within 5.74±3.36 years. On average, participants napped for 38.3±1.0 (SE) min and1.56±0.04 (SE) times per day at baseline. After adjustment for age, sex, and education, every 30‐min increase in daily napping duration was associated with a 20% increase in the risk of incident AD (95% confidence interval [CI]: 9%‐31%; p=0.0002). One more nap per day was associated with a 19% increase in the risk of AD (95% CI: 8%‐30%; p=0.0003). These associations remained after adjustment separately for BMI, depressive symptoms, vascular diseases/risk factors, and other actigraphy‐derived measures including total daily activity, total sleep time, sleep fragmentation, stability and variability of daily activity rhythms.ConclusionLonger and more frequent daytime naps are associated with a higher risk of incident AD. Future studies are needed to examine specific underlying mechanisms.
Equivalence of serum and plasma neurofilament light chain levels using highly sensitive automated immunoassay
Authors: Qiu Xiaolei , Lee Stephen , Jackson Jeremiah , Zhao Xingfang , Shields Aileen , Matias Madeleine , Uzgiris Arejas 
Published: December 2020

AbstractBackgroundNeurofilament light chain (NfL) in blood is a promising new biomarker for neurogenerative disease1 and clinical progression in presymptomatic Alzheimer disease2. Well established standardization of assays and collection methods are necessary before acceptance for clinical use. Data supporting equivalence of plasma and serum NfL testing are not yet widely published. In this study, we compared three blood collection specimen types, two for plasma and one for serum.MethodMatched serum, heparin‐treated plasma, and EDTA‐treated plasma from 40 individual donors were acquired. NfL concentration was determined using an automated immunoassay developed at Siemens Healthcare Laboratory, LLC3. Sample equivalence was analyzed with Deming regression.ResultAll two way comparisons resulted in strong correlation: NfL concentrations in serum and lithium heparin plasma (slope=1.004, R=0.971), serum and K2EDTA plasma (slope=1.065, R=0.961), and lithium heparin plasma and K2EDTA plasma (slope=1.059, R=0.979).ConclusionIndividual to individual variability was noted to be higher in plasma than with serum. With a well‐optimized automated immunoassay, NfL concentrations in plasma and serum were equivalent. References: (1) Zetterberg, H., Burnham, S.C. Blood‐based molecular biomarkers for Alzheimer’s disease. Mol Brain 12, 26 (2019) doi:10.1186/s13041‐019‐0448‐1. (2) Preische O, et al, Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease, Nat Med. 2019 Feb;25(2):277‐283. doi: 10.1038/s41591‐018‐0304‐3. (3) Plavina, et al, Development of a Sensitive Serum Neurofilament Light Assay on Siemens Routine Immunoassay Platforms, poster presentation, ECTRIMS, 2019.
The state of the science on synchronous video‐conferencing interventions for care partners of persons with dementia
Authors: Tarter Robin R. , Tran Leslie , Lindauer Allison 
Published: December 2020

AbstractBackgroundThe need for effective clinical interventions to prevent the potentially deleterious health impact of providing unpaid care to friends and family members with Alzheimer’s disease and related dementias (ADRDs) has become increasingly urgent. Synchronous video‐conferencing in which ADRD care partners interact in real time with trained healthcare professionals has emerged as an especially promising method for telehealth interventional research. Here we report on the designs and outcomes of such interventions for care partners of persons with ADRDs.MethodA scoping review was undertaken following Arksey and O’Malley’s systematic methodological framework. Articles were identified through a comprehensive search of PubMed, PsychINFO, and CINAHL. Inclusion criteria were peer reviewed, data‐based research articles published between 2015 and 2020 reporting results of synchronous video‐conferencing interventions specifically designed to address the needs of care partners of persons with ADRDs. Reviews, scale development, protocols, and case studies were excluded.ResultFull text screening of 159 articles resulted in the identification of seven articles reporting the results of six independent interventions. Included studies fell into two categories, psychoeducational behavior modification interventions delivered by nursing professionals and facilitated peer support interventions delivered by psychologists and social workers. Interventions varied based on technological mode of delivery, level of interaction among participants and between participants and interventionists, duration and frequency of sessions, and outcomes measured or described. Articles reported evidence of efficacy for decreasing care partner loneliness, depression, burden, and increasing care competence. Feasibility and acceptability of the technological interface varied between interventions, but was high overall.ConclusionBy comparing and contrasting these 6 synchronous video‐conferencing interventions, we are able support the viability of synchronous video‐conferencing as an effective mode of intervention for care partners of persons with ADRDs, and generate information to inform future research. Despite evidence that care partners need stage‐specific interventions, none of the reviewed studies were tailored to specific dementia stages, and there was a glaring lack of diversity in most study samples. Our results suggest that future research with care partners should not be limited to earth‐bound, face‐to‐face interventions, and that synchronous video‐conferencing has benefits above and beyond other approaches.
Audio‐visual speech perception is associated with cerebral tau deposition on [18F]flortaucipir PET
Authors: Risacher Shannon L. , Herbert Carolyn J. , Vosmeier Aaron , Garrett Makaylah N. , West John D. , Deardorff Rachael , Yates Charles W. , Apostolova Liana G. , Pisoni David B. , Saykin Andrew J. 
Published: December 2020

AbstractBackgroundSensory impairments are associated with dementia and biomarkers of pathology. In a preliminary study, we evaluated whether audio‐visual speech perception, which involves integration of complementary phonetic information from two sensory modalities (vision and hearing), is associated with AD neuropathology on imaging.Method14 individuals (2 cognitive normal (CN), 7 subjective cognitive decline (SCD), 4 MCI, and 1 AD) from the Indiana Alzheimer Disease Center and Indiana Memory and Aging Study underwent auditory testing, MRI, amyloid PET with [18F]florbetaben, and tau PET with [18F]flortaucipir. The audiologic testing included a brief pure‐tone hearing screen, followed by CUNY Sentences [1], among other tests. CUNY Sentences are presented using auditory input only (Auditory condition (A)) or using both auditory and visual input (AV using video with sound of an individual saying sentences). Words and sentences correct are scored, as is the difference between word and sentence scores (ΔWdtoSent). Amyloid and tau PET were processed using standard techniques. Mean SUVR from the cortex (amyloid and tau) and lateral temporal lobe (LTL; tau) were extracted. MRI was processed with Freesurfer v6 to extract LTL thickness. Because the CUNY scores were skewed, Spearman correlations were used to assess relations of sentence scores and ΔWdtoSent for both the A and AV conditions with neuroimaging measures of AD pathology (cortical amyloid, LTL and cortical tau, and LTL thickness). Inclusion of age, sex, and ICV where appropriate did not alter the observed results.ResultsSignificant associations between AV speech perception for sentences and AV ΔWdtoSent and tau deposition in the LTL and cortex were observed (Figure 1). These results remained significant after the AD participant was removed. Only trend associations were observed for the A condition, which were less robust than in the AV condition. Finally, a trend for a significant association with LTL thickness was observed. No association with amyloid was observed.ConclusionIntegration of phonetic information from two sensory modalities (vision and hearing) may be a potential a biomarker for tau pathology in patients at risk for AD. Future studies with larger samples and longitudinal follow‐up are needed. Reference: [1] Boothroyd et al. (1988) Ear and Hearing.
Proteomic interrogation of human hippocampal CA1 pyramidal neuron sublayers in Alzheimer’s disease
Authors: Reyes Isabel , Kanshin Evgeny , Ueberheide Beatrix , Masurkar Arjun V. 
Published: December 2020

AbstractBackgroundHippocampal CA1 pyramidal neurons (PNs) are highly vulnerable to Alzheimer’s disease (AD). There is increasing evidence that superficial and deep CA1 PNs are molecularly and functionally distinct. Yet, it is unknown if these sublayers show differential molecular profiles in human AD.MethodLaser capture microdissection was used to extract superficial and deep CA1 PN sublayers from hippocampal slices derived from formalin‐fixed, paraffin‐embedded (FFPE) Braak VI human AD brains (n = 8). Proteomics was performed using label‐free, quantitative liquid chromatography‐mass spectrometry (LC‐MS). Paired t‐test was used to identify protein hits whose abundance was significantly different (permutation‐based FDR correction, FDR cutoff at 5%) between neuron types.ResultLC‐MS on these samples was high yield, with detection of 3159 unique proteins spanning ∼6 orders of magnitude in abundance, with ∼15% of identifications related to synaptic and ion channel function. Differences between superficial and deep CA1 PN sublayers included those related to AMPAR regulation (SIRT2), synapse function (ARHGAP23, SEPTIN4), neurodegeneration markers (NEFH), and markers of late versus early vulnerability in AD (INA). Differences that were nearly significant included CNTN2, associated with hippocampal PN Kv1 channels, components of the postsynaptic density dysregulated in AD (DLG4 and variants), and KCTD16, which impacts GABAB currents.ConclusionProteomics combining LCM and LC‐MS from FFPE samples can be readily applied to address differences between PN sublayers. As such, these data support novel molecular differences between these layers in advanced AD, as related to physiologic dysfunction and disease‐related changes.