bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of convolutional neural network relevance maps for revealing patterns of Alzheimer’s disease in MRI scans
Authors: Dyrba Martin , Pallath Arjun H. , Teipel Stefan J. 
Published: December 2020

AbstractBackgroundAlthough machine learning approaches achieve high diagnostic accuracy for detecting Alzheimer’s disease (AD) based on MRI scans, they are not applied in clinical routine due to a lack of suitable methods for model comprehensibility and interpretability. Recently developed visualization methods for convolutional neural networks (CNN) may fill this gap. We trained a CNN model to detect AD based on T1‐weighted MRI and implemented a web application to provide an intuitive visualization of relevance maps. The aim of this study was to evaluate the association of relevance scores and hippocampus volume to validate the clinical utility of this approach.MethodMRI scans for 254 cognitively normal controls (CN), 219 patients with amnestic mild cognitively impairment (MCI), and 189 patients with AD were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). MRI scans were tissue‐segmented and normalized using VBM8. Hippocampal volume was extracted from the gray matter (GM) maps. Subsequently, GM maps and hippocampal volume were corrected for effects of total intracranial volume, age, gender and scanner magnetic field strength using a linear model. Thirty‐two coronal slices covering the hippocampus were selected and the corresponding GM residual maps entered into the CNN. The model was evaluated using ten‐fold cross‐validation. Finally, we derived activation maps using the layer‐wise relevance propagation (LRP) algorithm and calculated the sum of hippocampus relevance scores.ResultWe obtained highly accurate results of an AUC of 93±6% for AD vs. CN. For MCI vs. CN, group separation was lower with an AUC of 74±9%. The relevance maps for four exemplary patients are shown in Fig. 1. Relevance maps confirmed that hippocampal atrophy is the most informative region for AD detection with minor contributions from other cortical and subcortical regions. Relevance scores within the hippocampus were correlated with hippocampal volume with a Pearson correlation of r=‐0.79 (Fig.2).ConclusionOur CNN model yielded high accuracy when detecting AD and a medium level of accuracy for mild cognitive impairment. In general, the relevance maps showed the expected regions. The high association of hippocampus relevance scores and volume indicate a high validity of the CNN model as implemented in our intuitively usable web application.
Carotid atherosclerotic calcification characteristics relate to post‐stroke cognitive impairment
Authors: Wang Yingzhe , Li Shanshan , Ding Mengyuan , Dong Qiang , Yang Yemei , Cui Mei 
Published: December 2020

AbstractBackgroundPost‐stroke cognitive impairment (PSCI) is one of the major complications during the chronic stage of ischemic stroke. Several factors, including age, education level, vascular risk factors, extent of stroke, and cerebral small vessel disease, are considered to be main determinants of PSCI. However, the relationship between large vessel diseases and PSCI was less studied before. In this study, we aimed to investigate the association between different carotid atherosclerotic calcification characteristics and PSCI.MethodA total of 128 patients with acute ischemic stroke admitted to Huashan Hospital from 2017 to 2018 were included consecutively in this study. All of them completed brain/neck CTA and cognitive function battery at follow‐up. The number, size, location of calcifications in bilateral intracranial/extracranial internal carotid arteries, and the presence of rim sign was recorded separately. Quantitative analysis of arterial stenosis, reconstruction coefficient (RI) and soft plaque density was assessed as well. Cognitive function was evaluated 6‐12 months within the stroke onset. Post‐stroke cognitive impairment was diagnosed according to the cognitive questionnaires and CDR scale.ResultIn our study population, we found a prevalence of 58.6% for post‐stroke cognitive impairment with no dementia (PSCIND), and a prevalence of 20.3% for post‐stroke dementia (PSD). The presence of calcification on carotid arteries increased the risk for PSCI. Furthermore, in different calcification characteristics, multiple calcifications, thick/mixed calcifications and surface calcifications were significantly associated with PSCI after full adjustment (demographics, vascular risk factors and stroke severity). Carotid artery stenosis was another strong predictor for PSCI. However, rim sign, RI and soft plaque density showed no significant relationship with PSCI.ConclusionThe quantity and location of calcification might be independent indicators for PSCI in carotid atherosclerotic plaques.
Alzheimer pathology in the human ascending reticular activating system: Early and severe
Authors: Grinberg Lea Tenenholz 
Published: December 2020

AbstractBackgroundThe ascending reticular activating system (ARAS) is a collection of interconnected brain nuclei that regulates wakefulness, alertness and modulate behaviors. The critical components of ARAS degenerates early during Alzheimer’s disease progression in association with abnormal tau build‐up. Despite accumulating evidence, the role of AD‐related ARAS degeneration in promoting neuropsychiatric symptoms remains underappreciated. This talk will provide the state‐of‐the‐art in the knowledge of arousal system dysfunction in AD based on human studies as a framework for understanding the neuroanatomical changes underlying arousal dysfunction in AD.MethodWe reviewed authorial studies and results from other groups focusing on the isodendritic core of the reticular formation and other neuromodulatory nuclei associated with arousal in the context of AD pathology. Emphasis was given to quantitative studies, clinicopathological correlations and studies focusing on pre‐cognitive change, early AD stages.ResultMultiple nuclei of the ARAS, including the noradrenergic locus coeruleus, show consistent and early changes associated to AD‐type neuropathology build‐up, especially but not restricted to tau protein. These neuropathological changes lead to dysregulation of the respective neurotransmitter systems (both up‐ and downregulation) besides progressive neuronal dysfunction and death.ConclusionThe arousal neuromodulatory systems show early vulnerability to AD‐type changes. further understanding of the mechanisms leading to this vulnerability remains an unmet need and realizing this vision may point to strategies to treat neuropsychological symptoms in AD.
Noradrenergic responsiveness supports selective attention across the adult lifespan
Authors: Dahl Martin J. , Mather Mara , Sander Myriam C. , Werkle‐Bergner Markus 
Published: December 2020

AbstractBackgroundTheories of healthy and pathological aging assume a critical role of the locus coeruleus (LC), the main cortical norepinephrine (NE) supply, in shaping late‐life cognition. Postmortem analyses identified the LC as one of the first brain sites that accumulates tau pathology. However, in‐vivo research linking the noradrenergic system to senescent cognitive decline in humans is rare.Here we used a multimodal assessment to investigate whether individual differences in attention are related to the noradrenergic system.MethodIn younger (n = 39) and older adults (n = 38) we applied fear conditioning, an experimental manipulation known to modulate arousal‐related noradrenergic drive. Concurrently, we assessed pupil dilation, a non‐invasive proxy for noradrenergic activity, and the electroencephalogram (EEG) as indicators for successful NE manipulation. Reliable pupil and EEG signatures associated with elevated LC‐NE activity were identified in repeated conditioning sessions. We further evaluated participants’ general attention ability using a multimodal cognitive assessment. During one of the attention tasks (dichotic listening), fear‐conditioned (CS+) or perceptually matched control stimuli (CS–) were presented on a trial‐by‐trial basis to dynamically modulate arousal‐related noradrenergic drive.ResultRelative to younger adults, older adults demonstrated compromised performance across a variety of attention tasks. On a physiological level, presentation of fear‐conditioned stimuli during dichotic listening reinstated the acquired arousal response. Relative to control stimuli (CS–), conditioned stimuli (CS+) induced a multimodal response, consisting of pupil dilation and EEG desynchronization. Crucially, greater pupil dilation in response to the CS+ was associated with a stronger transient alpha–beta desynchronization (9–30 Hz), indicating a common dependence on phasic NE release. Using structural equation modeling, we integrated over EEG desynchronization and pupil dilation markers to derive a single index reflecting the responsiveness of the noradrenergic system to arousing stimuli. Combining behavioral and physiological data, we observed that a more responsive noradrenergic system was associated with better performance across attention tasks. Finally, we found that older age is associated with lower pupil‐ and EEG‐indexed noradrenergic responsiveness.ConclusionTaken together, our findings indicate that (1) noradrenergic neuromodulation dynamically sculpts low frequency oscillatory dynamics in posterior brain areas and (2) this interaction supports attention across the lifespan.
Working memory and mild cognitive impairment: Digital intra‐response latency, subcortical nuclei, and neuropsychological test performance
Authors: Emrani Sheina , Baliga Satya , Lamar Melissa , Price Catherine C. , Au Rhoda , Wasserman Victor , Matusz Emily , Swenson Rodney , Baliga Ganesh , Libon David J. 
Published: December 2020

AbstractBackgroundDigital technology offers the ability to obtain nuanced data previously unobtainable. A digital Backward Digit Span (BDT) using voice recognition was administered to memory clinic patients. Our goal was to assess the validity of this technology by (1) analyzing differences between non‐MCI versus MCI patients; (2) examining correlations with other neuropsychology tests; and, (3) analyzing test performance in relation to MRI subcortical regions of interest known to be related to working memory.MethodJak‐Bondi (2009) criteria classify patients into MCI (n= 67) and non‐MCI (n= 72) groups. Working memory (WM) was assessed with the Backward Digit Span Test (BDT) consisting of 7 trials of 5 digits backwards; all trials were administered; and comprehensive neuropsychological testing was obtained. Only correct test trials were analyzed. BDT variables of interest included latency for each five responses. NeuroquantTM software calculated thalamic, caudate and hippocampal volume (n= 23) controlled for intracranial volume (ICV).ResultBetween‐group difference for total time to completion was not significant (M= 55.64 + 18.91 sec.). An analysis of serial order position latencies clearly suggests two distinct epochs (Figure 1). A latency ratio (LR) for serial order 1 versus serial order 3 was calculated. Using this measure, non‐MCI patients presented with slower latency to initiate their response (serial order 1); but faster latency to sustain their response (serial order 3) compared that MCI patients (F[1,52]= 6.26, p< .016). Simple correlations were significant between the BDT‐LR and Judgement of Line Orientation Oblique test items (r= 0.325, p< .019) and WAIS‐III Digit Symbol test performance (r= 0.316, p< .017). Simple correlations were significant or near significant between the BDT‐LR and left thalamic volume (r= 0.468, p< 0.032); right thalamic volume (0.410, p< .065); total thalamic volume (r= 0.470, p< 0.032); and left caudate volume (r= 0.447, p< .042).ConclusionThese data are remarkable for how patients allocate their time to generate a correct response. Correlations between BDT‐LR, subcortical nuclei, and neuropsychological test performance provide evidence for the validity of using discrete latency measures to assess WM in patients with MCI. Intra‐response BDT latency ratios could be a meaningful neurocognitive biomarker for emergent illness.
Repeated memory‐based assessments: Implications for clinical trials and practice
Authors: Papp Kathryn V. , Samaroo Aubryn H. , Chou Hsiang‐Chin Lori , Buckley Rachel F. , Rentz Dorene , Sperling Reisa A. , Amariglio Rebecca 
Published: December 2020

AbstractBackgroundDetailed longitudinal neuropsychological assessment in the Harvard Aging Brain Study (HABS) and related studies has revealed that subtle decrements in associative and semantic memory, as well as reduced practice effects for repeated items may be the earliest cognitive changes in preclinical AD. Utilizing digital, repeated, and remote assessment of these cognitive functions has the potential to increase the rapidity and ease with which these subtle changes can be detected. We previously showed that diminished practice effects on a challenging iPad‐based monthly face‐name memory paradigm was associated with neuroimaging markers of amyloid and tau in normal older adults participating in HABS. These findings inspired the development of the Boston Remote Assessment of Neurocognitive Health (BRANCH), a smartphone‐based associative and semantic memory assessment using stimuli and tasks relevant to everyday life designed for serial assessment.MethodWe describe the development, feasibility, and pilot data from a smartphone‐based memory assessment administered daily (over consecutive days) in normal older adults using their own devices. BRANCH includes 2 measures of paired associative learning (faces and names, groceries and prices), an associative memory test with facilitated encoding (categories), and a continuous visual recognition task (street signs). A total of 41 pilot participants (mean age=76.1; 64% female) completed 1 version of BRANCH in clinic and 4 versions remotely on their own mobile device for 4 consecutive days. Participants also completed standard paper and pencil testing and a questionnaire about their experience completing the task.ResultBRANCH was feasible with a total of 80% of individuals completing all assessments in the correct order. It was acceptable to participants with 64% finding the tasks at‐least somewhat to highly engaging. Older age and general cognition (e.g., MMSE) was associated with worse performance across memory tasks. Improved performance (practice effect) was observed on daily administration of paired associative memory tasks (Figure 1.).ConclusionA theoretically and evidence‐based digital memory assessment with ecologically‐valid tasks and stimuli is feasible for older adults to complete independently on their own devices. Digital assessment over multiple timepoints has the potential to drastically improve the efficiency with which cognitive performance and subtle decline can be captured.
NOX4 negatively regulates memory functions in APP/PS1 mice
Authors: Zhu Xiaolei , Tao Wenyuan , Yu Linjie , Jin Jiali , Xu Yun 
Published: December 2020

AbstractBackgroundExcessive oxidative stress plays a critical role in the pathogenesis and progression of Alzheimer's disease (AD). Nox4 is constitutively active and widely expressed in the brains, and inhibition of Nox4 decreases the level of ROS and oxidative stress. Emerging evidence has shown that NOX4 inhibition protects against stoke and traumatic brain injury. However, the role of NOX4 in the pathogenesis of AD is not defined.MethodMale APPswe/PS1dE9 (APP/PS1) transgenic mice, NOX4‐/‐ mice and wild type C57BL/6 (B6) littermates were obtained from the Model Animal Research Center of Nanjing University. GLX351322 (5 mg/kg/day, MedChemExpress, USA), was intraperitoneally injected to APP/PS1 mice for 4 weeks followed by the behavior tests. The memory function was examined by Novel‐object recognition (NOR), Fear condition (FC) and Morris water maze (MWM) tests. The amyloid load was determined by immuofluorescence assay (IFA) and ELISA. Synaptic transmission was examined by hippocampal LTP induction and synaptic proteins were determined by IFA and western blotting. The markers of lipid peroxidation 4‐HNE, protein oxidation 3‐NT, and DNA oxidation 8‐OHdG were detected using the corresponding ELISA kits. The level of ROS and H2O2 was measured using the commercialized kits.ResultNox4 was mainly expressed in neurons in the central nerve system, and Nox4 inhibition by GLX351322 protected against Aβ1‐42 induced neurotoxicity. In addition, GLX351322 treatment attenuated memory deficits and synaptic dysfunction of APP/PS1 mice, and decreased the amyloid load and oxidative stress in the hippocampus of APP/PS1 mice. Furthermore, Nox4 knockout APP/PS1 mice showed improved memory functions and decreased amyloid load and oxidative stress, which was consistent with the results of GLX351322.ConclusionOur results have demonstrated that NOX4 inhibition or knockout attenuated memory deficits in APP/PS1 mice, suggesting that NOX4 might be a potential target for AD treatment.
Activation of Nav1.1 ameliorates tau pathology and brain atrophy in a mouse model of tauopathy
Authors: Sampei Kazuaki , Seki Chie , Takuwa Hiroyuki , Maeda Jun , Ono Maiko , Tokunaga Masaki , Shimojo Masafumi , Honda Shigeyuki , Kimura Taeko , Ishikawa Taizo , Kudo Takehiro , Takado Yuhei , Sahara Naruhiko , Higuchi Makoto 
Published: December 2020

AbstractBackgroundSeveral clinical studies indicate that subclinical epileptiform discharge is observed in patients with Alzheimer’s disease (AD), and neuronal hyperexcitability accelerates their cognitive decline. Previous studies indicated that the expression level of Nav1.1, which is coded by the Scn1a gene and a voltage‐gated sodium channel abundantly expressed in parvalbumin‐positive inhibitory neurons, decreased in AD patients. Because it is reported that excitatory neural activity stimulates tau release from neurons, we hypothesized that suppressing neuronal hyperexcitability by enhancing inhibitory neural activities could ameliorate disease progression in a mouse model of tauopathy. In this study, we investigated if our in‐house Nav1.1 potentiator, compound‐X, prevents the progression of tau accumulation and neurodegeneration in a mouse model of tauopathy, rTg4510.MethodWe performed electrophysiological recording to determine the specificity and potency of compound‐X in cells stably expressing various Nav subtypes, and cortical slices of Scn1a<+/‐> and rTg4510 mice. We subsequently tested the in‐vivo effects of compound‐X on Nav1.1 by examining if compound‐X can prevent hyperthermia‐induced seizure in Scn1a<+/‐> mice. To assess the effect of compound‐X on tau‐induced neuropathologies in rTg4510 mice, we orally treated rTg4510 mice with this compound from 4 months of age, and evaluated tau accumulation and brain atrophy of these animals by longitudinal tau PET with [18F]PM‐PBB3 and MRI, respectively, at 6 and 8 months of age.ResultThe auto‐patch‐clamp system using Nav stably expressing cells and current‐clamp recoding using cortical slices demonstrated that compound‐X could potentiate Nav1.1 current in a concentration‐dependent manner, leading to activation of inhibitory neurons. Scn1a<+/‐> mice administered with compound‐X showed an increased threshold of the rectal temperature of hyperthermia‐induced seizure, and prolonged latency to seizure, indicating that compound‐X can potentiate Nav1.1 in vivo. Significantly, tau accumulation and neuronal loss assessed by cerebral atrophy and lateral ventricular enlargement were profoundly suppressed in the brains of rTg4510 mice relative to vehicle‐treated controls.ConclusionPharmacological enhancement of inhibitory neuronal function can be a beneficial approach to the prevention of hyperexcitability‐mediated tau pathologies and neuronal death in a mouse model of tauopathy.
Automated lexical and acoustic analysis of young and older healthy adults
Authors: Cho Sunghye , Nevler Naomi , Shellikeri Sanjana , Parjane Natalia , Ryant Neville , Ash Sharon , Irwin David J , Cieri Christopher , Liberman Mark Y , Grossman Murray 
Published: December 2020

AbstractBackgroundLanguage use is affected by factors such as an individual’s age and sex. An understanding of these factors is essential to studies of speech in neurodegenerative disease. While age and sex have received considerable attention in the literature, results are mixed. Also, very few studies have considered both lexical and acoustic features at the same time, which leaves a major gap in our understanding of the effect of age and sex on language use. In this study, we analyze both lexical and acoustic features from 1‐minute speech samples using novel, objective, reproducible, fully automated methods.MethodWe examined digitized Cookie Theft picture descriptions produced by 37 older (52‐89y, mean=68y) and 76 young (18‐22y, mean=20y) participants. Using modern natural language processing and automatic speech recognition tools, we automatically annotated part‐of‐speech categories of all tokens and rated nouns and verbs for five lexical features, including word frequency, familiarity, concreteness, age of acquisition and semantic ambiguity. We automatically segmented each sample into speech and silent pause segments; extracted acoustic features such as total speech time, mean speech segment duration, and mean pause duration; and measured pitch percentiles from all speakers.ResultOlder speakers produced significantly more interjections (p=0.023), pronouns (p<0.001), and verbs (p=0.004), and fewer conjunctions (p=0.013), determiners (p=0.009), nouns (p=0.049), and prepositions (p=0.002) than young participants. Older speakers’ nouns and verbs were more familiar (nouns: p=0.008, verbs: p<0.001), more frequent (verbs only: p=0.002), and less ambiguous (nouns: p=0.049, verbs: p=0.057) compared to those of young speakers. Older speakers produced shorter utterances (p=0.001) with a lower type/token ratio for nouns (p=0.016) than young participants. Also, older participants produced shorter speech segments (p=0.017) and longer pauses (p<0.001) with increased total speech time (p<0.001) and total number of words (p=0.002). Lastly, we observed interactions of age and sex in pitch ranges (F(1,109)=4.37, p=0.039), the number of conjunctions (F(1,109)=9.52,p=0.003) and tense‐inflected verbs (F(1,109)=4.02, p=0.047).ConclusionThese results suggest that older speakers’ lexical content is less diverse and they use shorter utterances than young participants. The findings show that lexical and acoustic characteristics of semi‐structured speech samples can be examined using automated methods.
Increased accumbens volume predicts excessive daytime sleep in subjective cognitive decline with good sleep quality
Authors: Wang Ziqi , Dong Li , Yang Jie , Zhang Songge , Zhong Dayong , Han Ying , Yao Dezhong 
Published: December 2020

AbstractBackgroundThere is evidence of excessive daytime sleep (EDS) related to future Alzheimer’s disease, but little is known about what brain alterations in the very early stage of the disease. This study examines whether EDS is associated with specific brain volume alterations in subjective cognitive decline with good sleep quality.MethodStructural magnetic resonance imaging (MRI) was used to acquire anatomic scans from 109 community‐dwelling cognitive function normal participants (18 EDS, 91 control) and quantitative regional estimates of brain volume were derived by using volBrain. We adjusted analyses for age, sex, education, APOE, BMI, and intracranial volume.ResultEDS had significant increased volumes in left Thalamus, total Accumbens, right Accumbens and left Accumbens. Logistic analysis showed both total Thalamus and Accumbens, both left Thalamus and Accumbens related to diagnosis EDS. Only total Accumbens (r = 0.20, p = 0.039) and right Accumbens (r = 0.23, p = 0.018) associated with Epworth Sleepiness Scale (ESS) scores.ConclusionAt the preclinical stage, persons with increased Accumbens volume, even though had good sleep quality, predicts excessive daytime sleep.