Speech silence character as a diagnostic biomarker of early cognitive decline and its functional mechanism: a multicenter cross-sectional cohort study - BMC Medicine - BMC Medicine

Background

Language deficits often hap during the prodromal stages of Alzheimer’s illness (AD). However, the characteristics of linguistic impairment and its underlying mechanism(s) stay to beryllium explored for the aboriginal diagnosis of AD.

Methods

The percent of soundlessness duration (PSD) of 324 subjects was analyzed, including patients with AD, amnestic mild cognitive impairment (aMCI), and mean controls (NC) recruited from the China multi-center cohort, and the diagnostic ratio was replicated from the Pitt halfway cohort. Furthermore, the circumstantial connection web progressive successful the fragmented code was analyzed utilizing task-based functional magnetic resonance.

Results

In the China cohort, PSD accrued importantly successful aMCI and AD patients. The country nether the curve of the receiver operating diagnostic curves is 0.74, 0.84, and 0.80 successful the classification of NC/aMCI, NC/AD, and NC/aMCI+AD. In the Pitt halfway cohort, PSD was verified arsenic a reliable diagnosis biomarker to differentiate mild AD patients from NC. Next, successful effect to fluency tasks, clusters successful the bilateral inferior frontal gyrus, precentral gyrus, near inferior temporal gyrus, and inferior parietal lobule deactivated markedly successful the aMCI/AD radical (cluster-level P < 0.05, family-wise mistake (FWE) corrected). In the diligent radical (AD+aMCI), higher activation level of the close pars triangularis was associated with higher PSD successful in some semantic and phonemic tasks.

Conclusions

PSD is simply a reliable diagnostic biomarker for the aboriginal signifier of AD and aMCI. At arsenic aboriginal arsenic aMCI phase, the encephalon effect to fluency tasks was inhibited markedly, partially explaining wherefore PSD was elevated simultaneously.

Alzheimer’s illness (AD) is the astir communal neurocognitive disorder, with representation deficits being the earliest and astir diagnostic symptom, and this is accompanied by different cognitive deficits specified arsenic enforcement dysfunction, apraxia, and aphasia [1]. In the past fewer decades, large advancement has been made successful the improvement of biofluid oregon neuroimaging biomarkers for AD diagnosis, specified arsenic cerebrospinal fluid measures and successful situ imaging of Aβ and phosphorylated tau, different neuroimaging techniques, and neuropsychological tests [1]. However, these methods are constricted by their precocious outgo and invasive nature.

Language deficits are detected from the prodromal stages of AD oregon amnestic mild cognitive impairment (aMCI) and person been considered arsenic a campaigner biomarker for aboriginal diagnosis [2,3,4]. Most of these studies absorption either connected identifying diagnostic linguistic parameters oregon utilizing them to discriminate betwixt steadfast older radical and those affected by aMCI oregon AD, and they bespeak a ample fig of connection components with perfect diagnostic values for discriminating AD, yet results were heterogeneous owed to the assortment of methods and vocal features being examined [5], not to notation the imaginable influences of chiseled connection spoken by subjects, oregon adjacent the dialects of a peculiar language. And nary azygous biomarker accurately diagnoses each cases of AD. Among them, pauses are often investigated arsenic a hallmark of the lexical-semantic diminution during code accumulation successful AD [6, 7] and whitethorn beryllium the cardinal origin corresponding to code fluency which is chiefly determined by semantic and phonemic fluency [8].

Given that soundless pauses are progressive with impairment successful aggregate cognitive abilities, e.g., connection retrieval, moving memory, and execution, we enactment accent connected the astir important aspect—lexical-semantic processing and its functional alteration successful AD oregon aMCI [9]. Further, the intermission frequence successful picture-based communicative has been reported to beryllium associated with verbal fluency and grey substance density of anterior temporal lobe [2, 6, 10]. Although the task-based functional magnetic resonance imaging (fMRI) method is simply a fashionable method to visualize encephalon areas supporting circumstantial cognitive stimuli [11], to date, a constricted fig of studies person focused connected functional alteration connected the connection web and its narration with soundless pauses.

Our erstwhile survey suggested that the computer-based investigation of definite connection components could beryllium a promising diagnostic method for aboriginal AD and aMCI [2] and highlighted the exertion of percent soundlessness duration (PSD, successful which soundlessness is defined arsenic the summed duration of each soundless segments of the recording, chiefly the assorted pauses) arsenic a perchance reliable biomarker for the aboriginal signifier of cognitive diminution owed to AD with translingual diagnostic value. In bid to afloat find the translingual diagnostic worth of PSD and its related encephalon web alteration, we volition corroborate the diagnostic worth of PSD successful the Chinese multi-center cohort and further validate its diagnostic worth successful an English-speaking cohort from the Pitt database, and the encephalon networks progressive successful verbal fluency which are related to PSD utilizing a task-based fMRI experimentation volition beryllium explored.

Multi-center Chinese-speaking RSF cohort successful China

This is simply a cross-sectional study, with a full of 324 participants recruited from 3 representation clinics of hospitals successful China (hereafter termed the RSF cohort: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai; Shanghai Sixth Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai; the First Hospital Affiliated to Zhejiang University, Zhejiang), successful which 113 were NC (normal control), 95 were aMCI, and 116 participants were diagnosed with aboriginal signifier AD. The registration fig is ChiCTR2000036718 connected the website associated with this survey (https://www.chictr.org.cn). All participants (including the NC recruited among relatives of the aMCI and AD patients, with a petition for NC participants besides advertised) were recruited betwixt August 2020 and July 2021 from the representation session of the RSF cohort centers mentioned above. The authors asserted that each procedures contributing to this enactment comply with the ethical standards of the applicable nationalist and organization committees connected quality experimentation and with the Helsinki Declaration of 1975, arsenic revised successful 2008. All procedures involving quality subjects/patients were approved by the Ethics Committee of the RSF centers (approval number: 2020-261). All included individuals provided written consent.

Clinical appraisal successful the RSF center

To exclude different causes of cognitive impairment, we performed cranial MRI oregon computed tomography (CT) to exclude confounding factors specified arsenic changeable oregon intracranial space-occupying lesions. Serum folic acid, vitamin B₁₂ levels, and thyroid relation were tested to exclude endocrine and metabolic disorders. Clinical and demographic information including age, gender, and level of acquisition were besides collected. All subjects underwent neuropsychological tests including the following: the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment-Basic (MoCA-B), and Addenbrooke’s Cognitive Examination-III (ACE-III), scoring according to the Clinical Dementia Rating standard (CDR) and the Cookie-theft representation statement task from the Boston Diagnostic Aphasia Scales [12,13,14].

After objective assessment, the participants were categorized into 3 groups: (i) a NC group, who were considered arsenic cognitively steadfast aft the objective consultation; (ii) an AD group, whose diagnosis was based connected the objective probable criteria for diagnosis of AD issued by the National Institute connected Aging-Alzheimer’s Association workgroups successful 2011 [15]; and (iii) an aMCI group, successful which patients had a representation ailment corroborated by astatine slightest 1 informant, and a diagnosis was conducted utilizing the Petersen criteria [16]. Participants were excluded if they had immoderate different neurological diseases, immoderate systemic illness which tin pb to cognitive dysfunction, psychiatric disorders, oregon terrible proceeding oregon imaginativeness impairment.

English-speaking Cohort of the Pitt Center

The DementiaBank corpus, which is portion of the TalkBank project, was utilized successful the contiguous survey [17] and is an open-access database [4]. This corpus contained recordings of 104 controls and 208 dementia patients, from July 1983 to April 1988 (last modified successful November 2018) involving the participants fixed a representation statement task, which was primitively designed for the Boston Diagnostic Aphasia Examination. The task required each subordinate to picture events depicted successful the picture, the aforesaid arsenic performed by participants successful the China RSF halfway (Cookie Theft representation statement task). We absorption connected the connection quality of aMCI individuals, successful which astir volition person to AD respective years later. However, determination were chiefly mMCI (multi cognitive domain type) records and a deficiency of aMCI records successful the DementiaBank. So, we decided to usage individuals with mild AD with MMSE scores of implicit 24 to correspond the aboriginal signifier of AD, akin with the MMSE people scope of aMCI individuals successful the China multi-center cohort. There were 20 mild AD records aft excluding unavailable records (recordings with a noisy background, code clip of implicit 60 s, oregon incomplete recordings), and 21 NC records were randomly selected signifier the power corpus. The diagnostic criteria for “Possible AD” oregon “Probable AD” determination were arsenic specifically described successful the survey from Becker et al. [17]. In bid to beryllium accordant with the China RSF halfway and the erstwhile survey [18, 19], the samples with “Possible AD” and “Probable AD” labels are merged to constitute the AD radical successful our study.

Recording protocol and code analysis

Subjects successful the China RSF halfway performed a Cookie Theft representation statement task, during which they were fixed a representation and were told to sermon everything they could spot happening successful the representation successful 1 min portion being recorded. The mean clip duration of the records is 39.6 ± 17.7 s. The RSF cohort individuals’ code was recorded nether the pursuing configuration parameters of Cool Edit Pro software: a frequence of 160000 Hz, creating a 16-bit mono recording, and biology sound was constricted to nether 45 dB. The automatic code designation (ASR) bundle for cognitive impairment v1.3 (developed by our team, China Software Copyright fig 2016SR164680) for code investigation was used, according to our erstwhile survey [2]. The Pitt records (the mean clip duration of the records is 39.0 ± 17.4 seconds) were converted to the audio configuration parameters identical to the RSF signaling utilizing the Cool Edit Pro software. Each illustration was analyzed by ASR bundle for cognitive impairment utilizing v1.3 to extract the speech/silence parameters. The sum of each soundless periods divided by the full code clip is the explanation of PSD (ratio of full soundless intermission duration to full code duration), expressed arsenic a percentage. The explanation of basal parameters acceptable successful our bundle was according to Pakhomov et al. [20], who had developed the measurements of spontaneous code from the Cookie Theft representation statement task for patients with dementia. Silence is defined arsenic the summed duration of each soundless segments of the recording, including wide abbreviated pauses, wide agelong pauses, and hesitation-associated pauses.

Task-based fMRI experiment

From existent cohort successful the Shanghai Ruijin center, a full of 48 right-handed individuals were recruited for further fMRI study. Seventeen participants were mild AD patients, 15 were aMCI patients, and sixteen were NC. The inclusion and exclusion criteria were accordant with that of the existent cohort arsenic has been described above. In addition, patients with the pursuing conditions were excluded: (a) moderate-to-severe AD indicated by MMSE < 15; (b) speechmaking disablement (or illiteracy); (c) abnormal findings successful the encephalon MRI scan (e.g., tumors, stroke, hydrocephalus); (d) psychiatric disorders diagnosed by Diagnostic and Statistical Manual of Mental Disorders V (e.g., claustrophobia); and (e) refractive errors that cannot beryllium corrected by MRI-supported eyeglasses. In summation to the neuropsychological scales assessed described supra (MMSE, MoCA-B, ACE), MRI participants were further screened utilizing the Boston naming trial (BNT). Taking semantic and phonemic deficits into consideration, an fMRI verbal fluency task was adapted, arsenic was shown successful S Figure 1. The scanning protocol and processing methods are summarized successful the supplementary materials.

Statistical analysis

According our erstwhile survey [2], for continuous variables, normality and homogeneity of variance was tested. ANOVA (3 groups), oregon Student T trial (2 groups) was utilized for usually distributed variables with adjacent colonisation variance, and the non-parametric tests Kruskal-Wallis (3 groups) oregon Mann-Whitney U (2 groups) trial was utilized for variables with nonhomogeneous variance. When the differences were statistically important (P < 0.05) among 3 groups, station hoc aggregate comparisons were further made; erstwhile the variance was equal, the Bonferroni method was used; otherwise, the Kruskal-Wallis trial was used. Receiver operating diagnostic (ROC) curves were plotted for PSD by calculating the sensitivity and specificity of their diagnostic powerfulness successful NC, aMCI, and AD benignant dementia. To research the correlation betwixt the parameters, correlation investigation and stepwise aggregate linear regression were used. All statistical analyses were performed utilizing SPSS.

The objective characters of the subjects successful China RSF halfway and Pitt center

There were 113 NC, 95 aMCI, and 116 AD patients successful the China RSF multi-center cohort. Gender (female constitution successful NC: 62.8%, aMCI: 56.8%, and AD: 52.8%) and acquisition level (NC: 12.2 ± 2.9 years, MCI: 11.5 ± 3.1 years, and AD: 11.3 ± 3.5 years) showed nary important quality among the NC, aMCI, and AD groups successful the China RSF halfway cohort, and mean property was 67.6 ± 7.9, 73.0 ± 6.8, and 76.4 ± 8.2 years for the NC, MCI, and AD groups wrong this cohort (P < 0.001), respectively. However, determination were important differences betwixt groups’ mean MMSE scores (NC: 28.7 ± 1.2, MCI: 26.2 ± 2.3, and AD: 19.0 ± 4.2), MoCA-B (NC: 26.0 ± 2.5, MCI: 20.7 ± 3.6, and AD: 14.5 ± 4.7), ACE-III show (NC: 86.2 ± 7.4, MCI: 73.8 ± 9.3, and AD: 54.1 ± 13.6), and sub-items relating to fluency and connection (Table 1, each P < 0.001), and the post-hoc examination results are shown successful S Table 1.

Regarding the Pitt center, 20 mild AD patients (MMSE ≥ 24) and 21 NC individuals randomly selected had objective characteristics shown successful S Table 2. PSD was besides importantly antithetic betwixt NC and mild AD patients.

PSD arsenic a biomarker for aMCI and AD

In the China RSF halfway cohort, compared with NC subjects, aMCI and AD patients had importantly accrued PSD (Table 1, Fig. 1, P < 0.001), and PSD inversely correlated with cognitive show (Fig. 2, S Table 3, P < 0.001). Following linear regression analysis, the variables representing aMCI and AD presumption of individuals successful the cohort were importantly correlated with PSD aft adjusting for property (S Table 4). The ROC curves comparing PSD-based classification sensitivity and specificity among NC, aMCI, and AD patients are shown successful Fig. 1A–D. The AUCs of the curves are 0.74, 0.84, 0.80, and 0.65 successful NC/aMCI, NC/AD, NC/aMCI+AD, and aMCI/AD, and the sensitivity and specificity of NC/aMCI, NC/AD, NC/aMCI+AD, and aMCI/AD is 0.71/0.71, 0.84/0.70, 0.78/0.79, and 0.85/0.43 respectively. The optimal cutoff for PSD successful NC/aMCI, NC/AD, and NC/aMCI+AD was astir 38.0 for each classifier utilizing the SPSS ROC package. The organisation and examination of PSD successful NC, aMCI, and AD groups is presented successful Fig. 1E. In the Pitt halfway cohort, PSD was verified arsenic a biomarker to differentiate mild AD patients from NC (AUC of NC/mild AD is 0.70, Fig. 1F), and the quality successful mean PSD betwixt NC and mild AD patients was important (Fig. 1G, P = 0.018).

Fig. 1

ROC curves and examination of PSD among NC, MCI and AD patients successful the China RSF multi-center (A–E) and Pitt halfway cohorts (F, G). The AUC and cutoff for PSD were 0.74 and 38.2 successful NC/MCI (A), 0.84 and 38.0 successful NC/aMCI (B), 0.80 and 38.0 successful NC/aMCI+AD (C), and 0.65 and 58.5 successful aMCI/AD (D). The examination of PSD among NC, MCI, and AD (E, *P < 0.05 vs NC, ^#P < 0.05 vs aMCI) successful the RSF halfway and betwixt NC and mild AD patients (G, *P < 0.05 vs NC) successful the Pitt halfway cohort demonstrated an AUC of 0.70 with a PSD cutoff of 44.0 to separate NC from mild AD (F)

Fig. 2

The correlation investigation of PSD with cognitive performance. The heatmap (A) and the scatter dot of PSD with MMSE (B), MoCA (C), ACE-III (D), ACE-language fluency (E), and ACE-language-other (F)

Verbal fluency-based fMRI network

Demographic, neuropsychological, and connection characteristics of fMRI participants are shown successful S Table 5. There was nary quality successful age, sex distribution, nor acquisition level among the NC, aMCI, and AD groups (P>0.05). The results of neuropsychological assessments and PSD for the fMRI participants was accordant with that of the RSF Center cohort arsenic well.

Clusters showing important quality successful ANOVA investigation are presented successful Fig. 3 and S Table 6 (cluster-level P < 0.05, FWE corrected). In the semantic task (Fig. 3A), the highest foci were chiefly located astatine the bilateral precentral gyrus (PreCG), near pars opercularis (pOp) and pars triangularis (pTr), near mediate occipital gyrus (MOG), and close precuneus and pTr. There was a important affirmative correlation betwixt the BOLD signals of each clusters but the near pOp and semantic fluency sub-scores of ACE-III (S Table 7). In the phonemic task (Fig. 3B), areas activated otherwise crossed groups were confined to the near PreCG, inferior parietal lobule (IPL), inferior occipital gyrus (IOG) and close pTr. Among them, the near IPL, PreCG, and close pTr were recovered to beryllium associated with phonemic fluency sub-scores of ACE-III (S Table 7). In the station hoc investigation (Fig. 3C, D; S Table 8), we observed that successful some AD and aMCI astir each clusters showed singular deactivation successful examination with the NC radical (P < 0.05, Bonferroni corrected). Compared with aMCI, the effect of AD patients to fluency tasks successful astir of these clusters declined further but near pOp (P < 0.05, Bonferroni corrected), close pTr and PreCG (not significant) activated astatine a comparatively higher level. The results remained robust fundamentally erstwhile the age, gender, and acquisition level of subjects were regressed retired arsenic nuisance covariates. In addition, successful the semantic fluency–fixation contrasts, a clump successful the near cerebellum crus I was observed to deactivate successful AD/aMCI (S Fig. 2). No radical differences were detected successful different contrasts, i.e., repetition > fixation; phonemic fluency > fixation; semantic/phonemic fluency > repetition; semantic fluency > phonemic fluency.

Fig. 3

Group differences successful fluency tasks. Clusters that activated astatine antithetic levels among NC, aMCI, and AD successful the semantic task (A and C) and the phonemic task (B and D) are presented respectively (one-way ANOVA, voxel-level P < 0.001, cluster-level P < 0.05, FWE corrected). Coordinates of clusters are listed successful S Table 6. Results of partial correlation investigation betwixt PSD and BOLD signals of the clusters successful diligent radical (AD+aMCI) were presented successful E and S Table 7 (age and sex controlled). L, left; R, right; PreCG, precentral gyrus; pOp, pars opercularis; pTr, pars triangularis; MOG, mediate occipital gyrus; PreC, precuneus; ITG, inferior temporal gyrus; MFG, mediate frontal gyrus; IPL, inferior parietal lobule; IOG, inferior occipital gyrus. Superscript digits 1 and 2 (^{1, 2}) indicates the following: clusters successful the aforesaid anatomical region

Unexpectedly, successful the semantic task, the higher activation level of the close pTr was associated with the higher PSD successful AD and aMCI (R = 0.43, P = 0.0148). While controlling for the effect of property and gender, we recovered the correlation betwixt the close pTr and PSD was important successful some semantic and phonemic tasks (Fig. 3E, S Table 7). No important correlation was observed successful different clusters with PSD performance.

In the contiguous study, we performed a broad investigation of connection components successful NC, aMCI, and AD individuals, including diagnostic PSD successful some the China RSF multi-center cohort and the DementiaBank corpus of the Pitt center, with a task-based fMRI survey of the underlying functional neural substrates. Our results amusement that PSD was some delicate and circumstantial successful the diagnosis of aMCI and AD. Meanwhile, arsenic different broadside of code intermission (PSD), verbal fluency was progressive with functional alteration successful the connection web covering the bilateral PreCG, near ITG, and IPL, unneurotic with Broca’s country and its counterpart successful the close hemisphere.

Language impairment is simply a halfway diagnostic of AD [21]. Prior studies person shown a nexus betwixt AD grounds severity and declining code and connection capableness [3]. The information based connected code investigation of AD patients indicated that combined connection characteristics provided a diagnostic accuracy of implicit 80% [5]. The archetypal survey utilizing automatic code investigation to place MCI and AD patients compared the voices of steadfast older adults and patients with extracted features that showed important differences successful respective tasks and obtained the champion operation done machine-learning methods, with an accuracy of 79% [22]. Another survey utilized the features related to duration, code rate, articulation rate, and pauses to get a 78.8% accuracy for MCI [23]. Our erstwhile survey connected the combined connection characteristics of PSD showed this metric amended discriminated aMCI signifier NC with a constricted illustration size [2]. However, determination was a deficiency of a language-specific parameter wrong that illustration from aggregate centers which could transgress language-specific differences. Therefore, successful the contiguous study, results from a considerably larger illustration of NC, aMCI, and AD subjects successful a multi-center cohort and an further English-speaking validation cohort further confirmed that PSD arsenic a azygous parameter is simply a delicate indicator of aMCI and AD, some discriminated via an optimal PSD cutoff that achieves 80% accuracy (AUC of 0.8). The quality of PSD to discriminate mild AD was besides validated successful the Pitt halfway cohort. These results bespeak that PSD is simply a non-invasive and easy accessed reliable biomarker for diagnosis of early-stage AD and is not restricted to antithetic types of connection oregon dialect, successful some Chinese- and English-speaking populations. Although determination is important quality of PSD betwixt aMCI and AD, the mediocre AUC (aMCI/AD, 0.65) and specificity (aMCI/AD, 0.45) indicated that PSD could not good foretell aMCI owed to AD.

Compared with task-based tests of episodic representation and different cognitive domains, a connection task proved to beryllium much delicate and close successful aboriginal recognition of AD by fMRI [24]. To unveil the mechanics underlying the summation successful PSD successful AD/aMCI patients, we conducted a block-design fMRI paradigm focusing connected verbal fluency, due to the fact that pauses arsenic a imaginable cardinal origin correspond to code fluency, which is chiefly composed by semantic and phonemic fluency [8]. As it should be, the fMRI differences could inactive beryllium ascribed to functional alterations successful aggregate cognitive abilities; thus, we enactment accent connected discussing the clusters successful canonical areas supporting connection processing successful young adults oregon older adults [25,26,27]. Echoing the aforementioned studies [28,29,30], for patients with AD oregon aMCI, determination were less encephalon areas recruited successful the semantic-lexical processing, successful examination with mean aging. One unanticipated uncovering was that this benignant of deactivation had emerged astatine arsenic aboriginal arsenic aMCI phase, portion the corresponding symptoms did not go evident until the dementia signifier [31]. On the contrary, the accrued recruitment of encephalon resources successful effect to semantic tasks was recovered successful older NC with oregon without a precocious hazard of AD [32, 33], suggesting that physiological compensation successful aging whitethorn person disappeared astatine the aboriginal signifier of AD. In the semantic fluency task, clusters successful near pTr, ITG, and PreCG (the little portion astatine the junction with pOp, precisely), arsenic components of semantic web [26], deactivated markedly successful AD/aMCI patients, partially explaining wherefore semantic processing is disrupted [24]. Particularly, contempt the decreased activation of the near cerebellum associated with declining fluency scores, the relation it plays successful connection processing remains chartless [34]. Another absorbing uncovering was that compared with the aMCI group, Broca’s country and its homologous areas successful the close hemisphere successful AD patients activated astatine a comparatively higher level. Moreover, successful AD and aMCI, the activation level of the close pTr was positively related to PSD, suggesting it whitethorn person a important relation successful pause-related network. Different from the relation the near pTr play successful the connection function, the close pTr is considered to beryllium a hub portion supporting societal cognition and power web [35]. Plenty of studies person recovered that determination could beryllium other inter-hemisphere recruitment for the fluency task and a latent betterment of connection relation aft encephalon harm [36,37,38]. However, contrary to what is seen successful mean aging [33, 39], the reduced lateralization successful pTr/pOp of AD patients did not effect successful enhanced fluency show nor decreased code pause, which could beryllium amended interpreted arsenic a failed effort oregon “decompensation” of the connection network.

No radical differences were detected successful different contrasts, including repetition vs. fixation, semantic/phonemic fluency vs. repetition, and semantic vs. phonemic fluency. We expected this could effect from the information that successful older adults a much widely-distributed connection web has been recruited adjacent successful the resting-state [40, 41], making the effect to fixation, low- and high-difficulty tasks look astir the same.

References

Author notes

1. Hua-Long Wang, Ran Tang and Ru-Jing Ren contributed arsenic to this work.

Authors and Affiliations

1. Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China

   Hua-Long Wang, Ran Tang, Ru-Jing Ren, Hai-Lun Cui, Jin-Tao Wang, Xin-Yi Xie, Qiang Huang, Jian-Ping Li, Sheng-Di Chen & Gang Wang

2. Department of Neurology, The First Hospital of Hebei Medical University; Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Shijiazhuang, 050031, Hebei, People’s Republic of China

   Hua-Long Wang

3. Department of Biochemistry and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, 30322, USA

   Eric B. Dammer

4. Department of Gerontology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China

   Qi-Hao Guo

5. Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China

   Guo-Ping Peng

6. Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

   You-Min Zhang, Fu-Hua Yan & Na-Ying He

Contributions

HLW, RT, RJR, NYH, and GW were liable for the survey design. HLW, RT, RJR, QHG, GPP, HLC, YMZ, JTW, XYX, QH, and JPL were liable for the information postulation and verification. HLW, RT, and HLC were liable for the information analysis. HLW, RT, HLC, and GW were liable for the figures. HLW and RT were liable for the manuscript writing. RJR, EBD, QHG, GPP, HLC, YMZ, JTW, XYX, QH, JPL, FHY, SDC, NYH, and GW were liable for the manuscript captious review. HLW, RT, RJR, NYH, and GW had entree to each the information successful the study, and GW had last work for the determination to taxable for publication. The authors work and approved the last manuscript.

Corresponding authors

Correspondence to Na-Ying He oregon Gang Wang.

Ethics support and consent to participate

All procedures involving quality subjects/patients were approved by the Ethics Committee of the RSF centers. All included individuals provided written consent.

Consent for publication

Manuscript is approved by each authors for publication.

Competing interests

The authors state that they person nary competing interests.

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