Brain Communications

Abstract In vivo gold standard for the ante-mortem assessment of brain β-amyloid pathology is currently β-amyloid positron emission tomography or cerebrospinal fluid measures of β-amyloid42 or the β-amyloid42/β-amyloid40 ratio. The widespread acceptance of a biomarker classification scheme for the Alzheimer’s disease continuum has ignited interest in more affordable and accessible approaches to detect Alzheimer’s disease β-amyloid pathology, a process that often slows down the recruitment into, and adds to the cost of, clinical trials. Recently, there has been considerable excitement concerning the value of blood biomarkers. Leveraging multidisciplinary data from cognitively unimpaired participants and participants with mild cognitive impairment recruited by the multisite biomarker study of Alzheimer’s Disease Neuroimaging Initiative, here we assessed to what extent plasma β-amyloid42/β-amyloid40, neurofilament light and phosphorylated-tau at threonine-181 biomarkers detect the presence of β-amyloid pathology, and to what extent the addition of clinical information such as demographic data, APOE genotype, cognitive assessments and MRI can assist plasma biomarkers in detecting β-amyloid-positivity. Our results confirm plasma β-amyloid42/β-amyloid40 as a robust biomarker of brain β-amyloid-positivity (area under curve, 0.80–0.87). Plasma phosphorylated-tau at threonine-181 detected β-amyloid-positivity only in the cognitively impaired with a moderate area under curve of 0.67, whereas plasma neurofilament light did not detect β-amyloid-positivity in either group of participants. Clinical information as well as MRI-score independently detected positron emission tomography β-amyloid-positivity in both cognitively unimpaired and impaired (area under curve, 0.69–0.81). Clinical information, particularly APOE ε4 status, enhanced the performance of plasma biomarkers in the detection of positron emission tomography β-amyloid-positivity by 0.06–0.14 units of area under curve for cognitively unimpaired, and by 0.21–0.25 units for cognitively impaired; and further enhancement of these models with an MRI-score of β-amyloid-positivity yielded an additional improvement of 0.04–0.11 units of area under curve for cognitively unimpaired and 0.05–0.09 units for cognitively impaired. Taken together, these multi-disciplinary results suggest that when combined with clinical information, plasma phosphorylated-tau at threonine-181 and neurofilament light biomarkers, and an MRI-score could effectively identify β-amyloid+ cognitively unimpaired and impaired (area under curve, 0.80–0.90). Yet, when the MRI-score is considered in combination with clinical information, plasma phosphorylated-tau at threonine-181 and plasma neurofilament light have minimal added value for detecting β-amyloid-positivity. Our systematic comparison of β-amyloid-positivity detection models identified effective combinations of demographics, APOE, global cognition, MRI and plasma biomarkers. Promising minimally invasive and low-cost predictors such as plasma biomarkers of β-amyloid42/β-amyloid40 may be improved by age and APOE genotype.

Duygu Tosun

Dallas Veitch

Paul Aisen

Clifford R Jack

William J Jagust

Ronald C Petersen

Andrew J Saykin

James Bollinger

Vitaliy Ovod

Kwasi G Mawuenyega

Randall J Bateman

Leslie M Shaw

John Q Trojanowski

Kaj Blennow

Henrik Zetterberg

Michael W Weiner

Detection of β-amyloid positivity in Alzheimer’s Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers

阿尔茨海默病神经影像学计划参与者中β-淀粉样蛋白阳性检测与人口统计学、认知功能、MRI及血浆生物标志物的关系

Abstract Olfactory dysfunction, or hyposmia, frequently occurs as a prodromal symptom and ongoing sign of Parkinson’s disease. Functional MRI is a powerful tool for studying functional changes in the olfactory brain regions in patients with Parkinson’s disease. However, existing studies show inconsistent results and no study has measured olfactory functional MRI abnormalities in the human olfactory bulb directly. This is mainly due to the well-known susceptibility artifacts in conventional functional MRI images that affect several key olfactory-eloquent brain regions, and especially the olfactory bulb. In this study, olfactory functional MRI was performed using a recently developed functional MRI approach that can minimize susceptibility artifacts and measure robust functional MRI signals in the human olfactory bulb during olfactory stimulation. Experiments were performed on high magnetic field (7T) in 24 early (&amp;lt; 5 years of parkinsonian symptoms) Parkinson’s disease patients and 31 matched healthy controls. Our data showed increased functional MRI signal changes (ΔS/S) in the olfactory bulb in patients with early Parkinson’s disease, which correlated with behavioral olfactory measures. Temporally, functional MRI signals in the olfactory bulb returned to the pre-stimulus state earlier after reaching peak amplitude in patients with early Parkinson’s disease, implicating a faster olfactory habituation effect. The piriform cortex showed reduced numbers of activated voxels in patients with early Parkinson’s disease, which correlated with behavioral olfactory assessment. Several secondary olfactory regions including the orbitofrontal cortex, temporal pole, and amygdala exhibited reduced numbers of activated voxels and increased functional MRI signal changes in patients with early Parkinson’s disease. Our data also showed that functional MRI results are highly dependent on voxel selection in the functional analysis. In summary, we demonstrate differential spatial and temporal characteristics of olfactory functional MRI signals between the primary and secondary olfactory regions in patients with early Parkinson’s disease. These results may assist the development of novel quantitative biomarkers (especially in the early stages of Parkinson’s disease) to track and predict disease progression, as well as potential treatment targets for early intervention.

Yu Luo

Xinyuan Miao

Suraj Rajan

Adrian G Paez

Xinyi Zhou

Liana S Rosenthal

Alexander Pantelyat

Vidyulata Kamath

Jun Hua

Differential functional change in olfactory bulb and olfactory eloquent areas in Parkinson’s disease

帕金森病中嗅球和嗅觉相关区域的差异性功能改变

Freezing of gait is a common and debilitating symptom in Parkinson’s disease. Although high-frequency subthalamic deep brain stimulation is an effective treatment for Parkinson’s disease, post-operative freezing of gait severity has been reported to alleviate, deteriorate or remain constant. We conducted this study to explore the optimal stimulation sites and related connectivity networks for high-frequency subthalamic deep brain stimulation treating freezing of gait in Parkinson’s disease. A total of 76 Parkinson’s disease patients with freezing of gait who underwent bilateral high-frequency subthalamic stimulation were retrospectively included. The volumes of tissue activated were estimated based on individual electrode reconstruction. The optimal and sour stimulation sites were calculated at coordinate/voxel/mapping level and mapped to anatomical space based on patient-specific images and stimulation settings. The structural and functional predictive connectivity networks for the change of the post-operative Freezing of Gait-Questionnaire were also identified based on normative connectomes derived from the Parkinson’s Progression Marker Initiative database. Leave-one-out cross-validation model validated the above results, and the model remained significant after including covariates. The dorsolateral two-thirds of the subthalamic nucleus was identified as the optimal stimulation site, while the ventrocentral portion of the right subthalamic nucleus and internal capsule surrounding the left central subthalamic nucleus were considered as the sour stimulation sites. Modulation of the fibre tracts connecting to the supplementary motor area, pre-supplementary motor area and pedunculopontine nucleus accounted for the alleviation of freezing of gait, whereas tracts connecting to medial and ventrolateral prefrontal cortices contributed to the deterioration of freezing of gait. The optimal/sour stimulation sites and structural/functional predictive connectivity networks for high-frequency subthalamic deep brain stimulation treating freezing of gait are identified and validated through sizable Parkinson’s disease patients in this study. With the growing understanding of stimulation sites and related networks, individualized deep brain stimulation treatment with directional leads will become an optimal choice for Parkinson’s disease patients with freezing of gait in the future.

Houyou Fan

Zijian Guo

Yin Jiang

Tao Xue

Zixiao Yin

Hutao Xie

Yu Diao

Tianqi Hu

Baotian Zhao

Delong Wu

Qi An

Yichen Xu

Yuan Gao

Yutong Bai

Jianguo Zhang

Optimal subthalamic stimulation sites and related networks for freezing of gait in Parkinson’s disease

帕金森病步态冻结的最佳丘脑底核刺激位点及相关网络

Abstract Data-driven machine-learning methods on neuroimaging (e.g. MRI) are of great interest for the investigation and classification of neurological diseases. However, traditional machine learning requires domain knowledge to delineate the brain regions first, followed by feature extraction from the regions. Compared with this semi-automated approach, recently developed deep learning methods have advantages since they do not require such prior knowledge; instead, deep learning methods can automatically find features that differentiate MRIs from different cohorts. In the present study, we developed a deep learning-based classification pipeline distinguishing brain MRIs of individuals with one of three types of headaches [migraine (n = 95), acute post-traumatic headache (n = 48) and persistent post-traumatic headache (n = 49)] from those of healthy controls (n = 532) and identified the brain regions that most contributed to each classification task. Our pipeline included: (i) data preprocessing; (ii) binary classification of healthy controls versus headache type using a 3D ResNet-18; and (iii) biomarker extraction from the trained 3D ResNet-18. During the classification at the second step of our pipeline, we resolved two common issues in deep learning methods, limited training data and imbalanced samples from different categories, by incorporating a large public data set and resampling among the headache cohorts. Our method achieved the following classification accuracies when tested on independent test sets: (i) migraine versus healthy controls—75% accuracy, 66.7% sensitivity and 83.3% specificity; (2) acute post-traumatic headache versus healthy controls—75% accuracy, 66.7% sensitivity and 83.3% specificity; and (3) persistent post-traumatic headache versus healthy controls—91.7% accuracy, 100% sensitivity and 83.3% specificity. The most significant biomarkers identified by the classifier for migraine were caudate, caudal anterior cingulate, superior frontal, thalamus and ventral diencephalon. For acute post-traumatic headache, lateral occipital, cuneus, lingual, pericalcarine and superior parietal regions were identified as most significant biomarkers. Finally, for persistent post-traumatic headache, the most significant biomarkers were cerebellum, middle temporal, inferior temporal, inferior parietal and superior parietal. In conclusion, our study shows that the deep learning methods can automatically detect aberrations in the brain regions associated with different headache types. It does not require any human knowledge as input which significantly reduces human effort. It uncovers the great potential of deep learning methods for classification and automatic extraction of brain imaging–based biomarkers for these headache types.

Md Mahfuzur Rahman Siddiquee

Jay Shah

Catherine Chong

Simona Nikolova

Gina Dumkrieger

Baoxin Li

Teresa Wu

Todd J Schwedt

Headache classification and automatic biomarker extraction from structural MRIs using deep learning

头痛分类与基于深度学习的结构MRI自动生物标志物提取

Abstract Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer’s disease, including APOE-ε4, APOE-ε2, and Alzheimer’s disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to APOE genotypes (N=1,541) and AD-PRS (N=1,093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age=66 years, SD=9.6) and an average of 5.3 years of MRI follow-up (max=24 years). Atrophy on volumetric MRI scans was quantified in 3 ways: (1) a composite score of regions vulnerable to Alzheimer’s disease (SPARE-AD), (2) hippocampal volume, and (3) a composite score of regions indexing advanced non-Alzheimer’s disease related brain aging (SPARE-BA). Global white matter hyperintensity volumes were derived from FLAIR MRI. Using linear mixed effects models, there was an APOE-ε4 gene-dose effect on atrophy in the SPARE-AD composite and hippocampus, with greatest atrophy among ε4/ε4 carriers, followed by ε4 heterozygouts, and lowest among ε3 homozygouts and ε2/ε2 and ε2/ε3 carriers, who did not differ from one another. The negative associations of APOE-ε4 with atrophy were reduced among those with higher education (p’s&amp;lt;0.04) and younger baseline ages (p’s&amp;lt;0.03). Higher AD-PRS were also associated with greater atrophy in SPARE-AD (p=0.035) and the hippocampus (p=0.014), independent of APOE-ε4 status. APOE-ε2 status (ε2/ε2 and ε2/ε3 combined) was not related to baseline levels or atrophy in SPARE-AD, SPARE-BA, or the hippocampus, but was related to greater increases in white matter hyperintensities (p=0.014). Additionally, there was an APOE-ε4 x AD-PRS interaction in relation to white matter hyperintensities (p=0.038), with greater increases in white matter hyperintensities among APOE-ε4 carriers with higher AD-PRS. APOE and AD-PRS associations with MRI measures did not differ by sex. These results suggest that APOE-ε4 and AD-PRS independently and additively influence longitudinal declines in brain volumes sensitive to Alzheimer’s disease and synergistically increase white matter hyperintensity accumulation among cognitively normal individuals. Conversely, APOE-ε2 primarily influences white matter hyperintensity accumulation, not brain atrophy. Results are consistent with the view that genetic factors for Alzheimer’s disease influence atrophy in a regionally-specific manner, likely reflecting preclinical neurodegeneration, and that Alzheimer’s disease risk genes contribute to white matter hyperintensity formation.

Anja Soldan

Jiangxia Wang

Corinne Pettigrew

Christos Davatzikos

Guray Erus

Timothy J Hohman

Logan Dumitrescu

Murat Bilgel

Susan M Resnick

Leonardo A Rivera-Rivera

Rebecca Langhough

Sterling C Johnson

Tammie Benzinger

John C Morris

Simon M Laws

Jurgen Fripp

Colin L Masters

Marilyn S Albert

Alzheimer disease genetic risk and changes in brain atrophy and white matter hyperintensities in cognitively unimpaired adults

阿尔茨海默病遗传风险与认知未受损成年人脑萎缩和白质高信号变化的关系

This scientific commentary refers to ‘Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment’, by Kaiyrzhanov et al. (https://doi.org/10.1093/braincomms/fcae453).

Shamima Rahman

Complex I deficiency remains the most frequent cause of Leigh syndrome spectrum

复杂I型缺陷仍然是 Leigh 综合征谱系中最常见的病因

Abstract A key question for the scientific study of consciousness is whether it is possible to identify specific features in brain activity that are uniquely linked to conscious experience. This question has important implications for the development of markers to detect covert consciousness in unresponsive patients. In this regard, many studies have focused on investigating the neural response to complex auditory regularities. One noteworthy example is the local global paradigm, which allows for the investigation of auditory regularity encoding at the ‘global’ level, based on the repetition of groups of sounds. The inference of global regularities is thought to depend on conscious access to such complex auditory stimuli as mostly shown in chronic stages of disorders of consciousness patients. However, whether global regularity encoding can identify covert consciousness along the consciousness spectrum including earlier stages of these disorders remains controversial. Here, we aim to fill this gap by investigating whether the inference of global auditory regularities can occur in acute coma, in the absence of consciousness, and how this may be modulated by the severity of the patients’ clinical condition and consciousness level measured using the Full Outline of UnResponsiveness (FOUR) score. We will acquire 63-channel continuous electroencephalography to measure the neural response to global auditory regularity in comatose patients (N=30) during the first day after cardiac arrest, when patients are unconscious, sedated and under normothermia, and during the second day (with reduced or absent sedation and body temperature control). We hypothesize that global regularity encoding will persist in the absence of consciousness independent of patient outcome, observed as above chance decoding of the neural response to global regularities using multivariate decoding analyses. We further hypothesize that decoding performance will positively correlate with the FOUR score, which indexes consciousness level, and typically improves between the first and second day after coma onset following cardiac arrest in patients with favourable outcome. In an exploratory analysis, we will also evaluate whether global regularity encoding may be influenced by the patients’ clinical management, specifically sedation, also shown to affect global deviance detection. Our results will shed light on the neurophysiological correlates of complex auditory regularity processing in unconscious patients and on the link to residual levels of consciousness during the underexplored state of coma upon the first days after cardiac arrest.

Andria Pelentritou

Jacinthe Cataldi

Frederic Zubler

Manuela Iten

Matthias Haenggi

Nawfel Ben-Hamouda

Andrea O Rossetti

Athina Tzovara

Marzia De Lucia

Complex auditory regularity processing across levels of consciousness in coma: Stage 1 Registered Report

昏迷中意识水平对复杂听觉规律处理的影响：第一阶段注册报告

Abstract We investigated semantic cognition in the logopenic variant of primary progressive aphasia (lvPPA), including (i) the status of verbal and non-verbal semantic performance; and (ii) whether the semantic deficit reflects impaired semantic control. Our a priori hypothesis that individuals with lvPPA would exhibit semantic control impairments was motivated by the anatomical overlap between the temporoparietal atrophy typically associated with lvPPA and lesions associated with post-stroke semantic aphasia and Wernicke’s aphasia, which cause heteromodal semantic control impairments. We addressed the presence, type (semantic representation and semantic control; verbal and non-verbal), and progression of semantic deficits in lvPPA. Since most people with lvPPA have Alzheimer’s disease pathology and are part of a broader multidimensional phenotype space encompassing Alzheimer’s disease subtypes, we compared semantic performance in lvPPA and typical amnestic Alzheimer’s disease. Given the differences in lesion and atrophy patterns in semantic aphasia and Wernicke’s aphasia versus semantic dementia/semantic-variant primary progressive aphasia patients, our second aim was to examine atrophy patterns in people with lvPPA and typical Alzheimer’s disease compared to age-matched controls. Twenty-seven patients participated in the study. People were grouped into those meeting consensus criteria for lvPPA (N = 10) and others who may have previously satisfied definitions of lvPPA but had progressed with multi-domain cognitive impairments (herein referred to as “lvPPA+”; N = 8). People with typical amnestic Alzheimer’s disease (N = 9) were relatively preserved across verbal and non-verbal semantic assessments. LvPPA patients were impaired on both verbal and non-verbal semantic tasks and their impairments showed the hallmark characteristics of a semantic control deficit. LvPPA and lvPPA+ patients showed effects of varying semantic control demands, positive cueing effects, and correlated performance between semantic and executive tasks. Whole-brain voxel-based morphometry, comparing each of the patient groups to age-matched controls, revealed significantly reduced grey and white matter in the bilateral hippocampi and lateral temporal regions in typical Alzheimer’s disease patients. The lvPPA group exhibited an asymmetric pattern of reduced grey and white matter intensity in the language-dominant left hemisphere, including a significant portion of the lateral and medial temporal lobe. LvPPA+ patients demonstrated reduced grey and white matter in the left temporal lobe extending subcortically, anteriorly and posteriorly, as well as right temporal involvement. Our findings could aid diagnostic subtyping of primary progressive aphasia by adopting semantic control features and offer improved clinical characterisation of lvPPA in the trajectory of semantic decline.

Shalom K Henderson

Siddharth Ramanan

Matthew A Rouse

Thomas E Cope

Ajay D Halai

Karalyn E Patterson

James B Rowe

Matthew A Lambon Ralph

Impaired semantic control in the logopenic variant of primary progressive aphasia

原发性进行性失语症语义性失语变异型的语义控制障碍

Abstract Co-pathology is frequent in Lewy body disease, which includes clinical diagnoses of both Parkinson’s disease and dementia with Lewy bodies. Measuring concomitant pathology in vivo can improve clinical and research diagnoses and prediction of cognitive trajectories. Tau PET imaging may serve a dual role in Lewy body disease by measuring cortical tau aggregation as well as assessing dopaminergic loss attributed to binding to neuromelanin within substantia nigra. We sought to characterize 18F-PI-2620, a next generation PET tracer, in individuals with Lewy body disease. We recruited 141 participants for 18F-PI-2620 PET scans from the Stanford Alzheimer’s Disease Research Center and the Stanford Aging and Memory Study, most of whom also had β-amyloid status available (139/141) from PET or cerebrospinal fluid. We compared 18F-PI-2620 uptake within entorhinal cortex, inferior temporal cortex, precuneus, and lingual gyrus, as well as substantia nigra, across participants with Lewy body disease [Parkinson’s disease (n=29), dementia with Lewy bodies (n=14)] and Alzheimer’s disease (n=28), in addition to cognitively unimpaired healthy older adults (n=70). Mean bilateral signal was extracted from cortical regions of interest in 18F-PI-2620 standard uptake value ratio (inferior cerebellar gray reference) images normalized to template space. A subset of participants received cognitive testing and/or the Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part III motor exam (off-medication). 18F-PI-2620 uptake was low overall in Lewy body disease and correlated with β-amyloid PET in temporal lobe regions and precuneus. Moreover, inferior temporal 18F-PI-2620 uptake was significantly elevated in β-amyloid positive relative to β-amyloid negative participants with Lewy body disease. Temporal lobe 18F-PI-2620 signal was not associated with memory in Lewy body disease, but uptake within precuneus and lingual gyrus was associated with worse executive function and attention/working memory performance. Finally, substantia nigra 18F-PI-2620 signal was significantly reduced in participants with Parkinson’s disease, and lower substantia nigra signal was associated with greater motor impairment. These findings suggest that although levels are lower than in Alzheimer’s disease, small elevations in cortical tau are associated with cognitive function in Lewy body disease relevant domains, and that reduced 18F-PI-2620 binding in substantia nigra may represent loss of dopaminergic neurons. Cortical tau and neuromelanin binding within substantia nigra represent two unique signals in the same PET image that may be informative in the context of cognitive and motor deficits, respectively, in Lewy body disease.

Joseph R Winer

Hillary Vossler

Christina B Young

Viktorija Smith

America Romero

Marian Shahid-Besanti

Carla Abdelnour

Edward N Wilson

David Anders

Aimara Pacheco Morales

Katrin I Andreasson

Maya V Yutsis

Victor W Henderson

Guido A Davidzon

Elizabeth C Mormino

Kathleen L Poston

18F-PI-2620 tau PET is associated with cognitive and motor impairment in Lewy body disease

18F-PI-2620 tau PET与Lewy体病中的认知和运动障碍相关

This scientific commentary refers to ‘The joint memory effect: challenging the selfish stigma in Huntington’s disease? ’, by Dalléry et al. (https://doi.org/10.1093/braincomms/fcae440)

Jan Van den Stock

Gert Cypers

François-Laurent De Winter

Mathieu Vandenbulcke

Preserved social facilitation and preferential processing of partner-relevant information in Huntington’s disease

在亨廷顿病中保留的社会促进和对伴侣相关信息的优先处理

Abbreviation	Brain. Commun.
Journal Impact	4.12
Quartiles(Global)	NEUROSCIENCES(Q2)

ISSN	2632-1297
h-index	34

Publication Information	Publisher: Oxford University Press，Publishing cycle: ，Journal Type: journal，Open Access Journals: Yes
Basic data	Year of publication: 2019，Proportion of original research papers: 95.92%，Self Citation Rate:2.40%， Gold OA Rate: 94.24%
Journal Fees	$Details
Average review cycle	网友分享经验：6 Weeks

Brain Communications

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