Neuroscience Lerters 747 (2021) 185672 Contents ists available at ScienceDiract Neuroscience Letters ELSEVIER Journal homepage: www.elsoviercomlocatelneulet Brain activity alterations in patients with Parkinson's disease with ‘one cognitive impairment based on resting-state functional MRI ‘Weina Guo®"', Wei Jin” ', Na Li’, Junshu Gao", Jiuxue Wang”, Yajun Chang’ Kuochang Yin, Yingmin Chen‘, Shugian Zhang ‘, Tianjun Wang * + pagar of Cit Sao ab Nar erty, Zara ne * tlgrment of Neo, Het Gen pel Sgr Cone Dips of Rog bl el pl Scag, Che ayo ‘bj Ths tidy sed 0 invite he diferencesinreglonal homogeneity (Ret) valves npn with gate inset Parkinson's escase (PD) with cogiive impaiment PD.) and this explore the newopatholgial mechanism aise’ ese D) weber 20 althycontos (Ca) in thi study The PD group comprited 2 patients with PELCL and 16 patents with PD ‘wth normal cogitive faction (PO-NG). The data were aalyeed wtng Reflo analy to chserve the changes in brain seit in pants with PDC and PDANC.Saistialeomparizn was performed sing covariance amas eau: The patients nthe PO-C group were older than thot in the PE-NC and HC group. Compared withthe 1 group, the PCI group showed hat the ello value decreased fa the ight supplementary motor ze, lft gual gyrus, left tala, abd let precaeus, Dut increased inte left fusfor yrus. Compared with the HC 0p the PD-NC group showed thatthe Reto value decreed in th ight cerebells 6, but neeasd inthe let inferior temporal gyrus, let obi inferior frontl gyms, and lf precental gyrus. Compared withthe PD-NC group, she PD-CI group showed that the Relo vale decreased inthe right recone, left trianguler inferior otal yet, let mide fora gyus, right opercular inferior fontl gyrus, left orbit! inferior festa gyrus left supramarginal gyrus left angulae gyrus, le nero temporal gyrus, an ight exrebelu, 7, but increased. inthe let presenta rvs andl asorm gy Conca: Age sa ik eco for cognitive decline n pavens with PD, The Re wef the det mode network (DN) sae closely related to PD cognitive futon, andthe DMN was affected before Clana contin ‘ously deteriorate ith disease progresion. Te disorder of vs condction pate was involved in Lin patients with PD, bt these patients could recat cognitive resources by improving vinsl-spata sity. The 1, Introduction increasing attention. tis found in upto 42.5% of patients with PD in the carly stages of the discase[2]. Up to 80% of the patients eventually Parkinson's disease (PD) isthe second mast common neurodegen- develop PD dementia (PDD) in the advanced stages ofthe disease] erative disorder characterized by motor symptoms, such as bradyki- which severely affects the prognosis of patients and increases the burden nesia, rigidity, and tremor, and the non-motor symptoms (NMS), on caregivers and overall medical costs. However, the pathogenesis of including neuropsychiatric disturbances and autonomic dysfunetion{:]. PD with CI (PD-Ci is unclear. Cognitive impairment (C1), as one of the NMS of PD, has attracted ‘Regional homogeneity (ReHo), as one of the methods for analyzing mal erent wangtinn;2007@ 126com (F- Wang) "These authors contibted equally to this work Gt fit authors) (0504.9940/6 2021 Fsevier BV Al ight reveredthe local activity data of restingstate functional magnetic resonance Imaging (-0R1), was proposed by Chinese scholars Zang and col- leagues). The Kendall's coefficient of concordance (KCC) among MRI time series ofa certain voxel and its surrounding voxels were calculated and assigned to each voxel to evaluate the similarity of intensity changes Of MR signals in the same time series, indirectly reflecting the simi- larity of changes in local funetiona activites of certain brain aeast: Let al, reported abnormal Rell values in patients with PD with mild cogaltive impairment (PD-MCI) within the default mode network (DMN), salience networks, and posterior cerebellar Tobe, which medi- ated cognitive function(s}. Moreover, Zhang e& al. observed diversifi- cation in spontaneous brain activity inpatients with Alzheimer's disease and MCI compared with normal controls using Retlo analysis(7]. A few Retlo-elated studies were conducted on patients with PD-Cl at home and abroad. Thus, ReHo analysis was used in che present study to investigate the change in the local activities in the brain between pa- tients with PD-Cl and PD-NC and evaluate the correlation between the Reo value and Montreal Cognitive Assessment (MoCA) scores of pa- tients with PD. 2. Materials and Methods 2.1. Partepants A total of 36 patients with PD admitted to and treated in the Depactment of Neurology of Hebei General Hospital from May 2018 to December 2019 were included inthis study. Al the patients presented a linical diagnostic riterion of idiopathic PD based onthe UX Brain Bank DD criteria( 8), excluding patients with Parkinsonian and Parkinson-plus syndrome. After MRI scanning, the patients were evaluated using the Unified PD Rating Scale (UPDRS), Beijing Version of MoCA, and Hochn-Vabr stage (H-¥). All inspection items were assessed 6 h after drag withdrawal ‘According to MoCA scores, patients with PD were divided into two subrypes: PD-Cl group and PD-NC group. Patients whose MoCA score ‘was >26 were deemed tobe patients with PD-NC, and others deemed to ‘e patients with PD-C. During the same peciod, 20 HCs with matched age, sex, and MoCA scone >26, including 12 men and 8 women, were recruited from the Hebei General Hospital medical examination center. The inclusion extera forall participants inthe study were a follows rightanded, aged 40-80 years, with the ability to give informed con- sent, The exclusion criteria were a fllows: contrandications to MRL scanning and routine MRI examination result showing other abnor- malities except for a small amount of high signal in the deep white ‘matter of fluidattensated inversion recovery (FLAIR)/T2-weighted image (T2WD sequence (Fazekas grade < 1D; severe diabetes, hyper- tension, cerebrovascular disease, or other diseases that cause cognitive decline, suchas brain traums or history of neurosurgery severe anxiety, tor depression diseases; and alcoholism and contraceptive use. All par ticipants were informed of the research protocol and signed the informed consent form, 2.2. MRI scanning Images were acquired on a GE 3.0 T MRI system (Discovery MR750v, GE Medical Systems, USA). For the seanning procedure, the paricipants lay awake on the examination tale. A foam padding was used to minimize head motion, and earplugs were used to reduce seanner noise. conventional T2WI [repetition time (VR) =4840 ms, echo time (TE) 102 ms eld of view (FOV) ~ 24 x 24 em matrix size 416 » 416] was fist oblained to exclude the patients with space occupied lesions, cerebrovascular diseases, obvious patehy hyper intensity on T2W1, or focal parenchymal loss. Then, during {MRI scanning, the participants were instructed to relax, keep their eyes closed, stay awake, and remain ail, while no apeciic task was per- formed, Functional images were obtained using a gradient recalled eco arsine ets 747 (2021) 198672 ccho-planar imaging (EPI) sequence (TR =2000 ms; TE =30 ms flip angle — 90; 35 slicer slice thickness ~ mm, without a gap; FOV ~ 24 = 24 em®; matrix size = 256 x 256), and 200 continuous axial EPI fone- tional volumes were acquired. The scanning lasted for 6 min and 40 s Seructural MRI scenning was performed using a Tl-weighted 3D-FSPGR Sequence (TR =8.50 ms; TR =3.3 ms; FOV = 24 x 24 em; matrix size = 64 x 64; slic thickness = I mm, without a gap). The scanning durtion was 3 min and $0 8 23. Data preprocessing ‘The r-{MIRI data were analyzed using the data processing & analysis of brain imaging (DPABI,hii/sirors/dpai) with Staitical Para- metric Mapping, version 12 (SPMI2, hitp://www-fiLion.ucLac.uk/5 running under MATLAB (R2018a) (The Mathworks, MA, USA). The preprocessing steps were a5 follows: (1) removal ofthe first 10 time Points; (2) slice timing; (3) head motion correction; (4) space normal- zation; (3) resampling 10 3-mm isotopic voxels; (6) linear deteended removal and temporal bandpass tering (0.01-0.08 Ha); and (7) space smoothening. The participants were excluded from further analysis if {he translation or rotation of head movement was >2 mm oF >2° in any dieetion. Two patients with PD-Cl were exchuded due to high levels of head motion ding seanning 24, Rebio analyse Individual Reto maps were generated for each participant using DDPABL. KCC was calculated at each voxel to establish similarities be- tween the time series ofeach specie voxel and its 26 neighboring voxels ‘within 2 whole-brain mask (this mask was provided by DPARSFA, excluding non-beainareas)(9} ‘he KCC value was calculated for this voxe, and an individual KC map was obtained for each paticipant. To reduce the influence of in dividval variations in the KOC valve, Rello map normalizations were performed by dividing the KCC among each voxel by the averaged KCC. ofthe whole brain (using the same whole-brain mask). The calibrated Reto maps were further smoothened using anisotropic Gausian kernel with full-width at half maximum (FWNM) of x 6 x 6mm’. Statistical analysis was caried out forthe inal Reto graph, 2. Statistical analysis Data were statistically analyzed using the Statistical Package forthe Socil Sciences (SPSS) 26.0, The sex of the patients belonging to the PD- 1, PD.NC, and HC groups was compared using the chi-squared test. ‘Moreover, age and education level were compared through analysis of variance, and multiple comparison correction was carried out using the Bonferroni test The MoCA scores were compared through analysis sing the Kruskal-Wallis test. A comparison ofthe course duration, UPDRS I scores, and H-Y stage between the PD-CI and PD-NC groups were per- formed using the Wilcoxon rank-sum test, with a P value <0.05 ind cating statistical significance. The measurement data that conformed 19 the normal distribution was expressed in mean = standard deviation, and other data that conformed to the non-normal distribution were expressed as median (fst quartile spacing P25 and second quartile spacing P73) “Analysis of covariance (ANCOVA) was performed using DPABI 10 compace the differences in ReHlo values among three groups, with sex, age, csease duration, education, gray matter volume, and average head motion parameters as covariates. The Gaussian random field (GRP) theory was used for clster-level multiple comparison correction (voxel P 0.001, luster P <0.05, two taled, and a minimum cluster size of 22 voxels, and the bran regions with asatistiealdiference were used as the mask of the ANCOVA posthoc ¢ test. Post-hoe comparisons were analyzed using the two-sample t test, and multiple comparison correc: tion was carried out using the GRF theory. Voxel P< 0,001 and cluster P<< 005 (tw tall) were ser (a minimum cluster size of 13 voxels) to Indicate statistical significance. Tae ReHo values ofthe two major PD subtypes wore extracted from the data, and the correlation analysis between the z values and the MoCA scores wae conducted using SPSS 26,0. AP value < 0.01 was st to indicate statistical significance. 3, Results 3.1. Demography and clinical characteristics [No statistically significant differences were found in ex and educa- tion among the three groups, However, age and MoCA scores exhibited significant differences on comparison of PD-CI versus PD-NC, and PD-Cl versus HGS, showing thatthe patients inthe PD-Cl group had higher age (P =0.001) and lower MoCA scores ( = 0.000) compared with patients in the other two groups. No significant diferences were observed be- tween the PD.Cl and PD-NC groups in terms of disease duratlon, UPDRS I or HY score (P > 0.05) Cable 1), 3.2. Rello ancyss ANCOVA reveled that the Reto values among the PD-MCI, PD-NC, and HC groups were significantly different inthe fllowing regions: the ‘ight hippocampus, right superior medial frontal gyrus, left wiangular Inferior frontal gyrus, right opereular inferior frontal gyrus, lft supra- ‘marginal gyrus, left middle occipital gyrs, right angular gyrus, loft orbital inferior frontal gyrus, and lft celearne ‘The ReHo value decreased in the right supplementary motor area, left ingual gyrus, left thalamus, and lft preeuneus, but increased inthe lett fusiform gyrus, in the PD-CI group compared with the HC group (Grable 2 and Fig. 0. The Rett value decreased inthe right cerebellum, 6, but increased in the let inferior temporal gy, lft orbital inferior frontal gyrus, and left preeentral gyrus, in the PD-NC group compared with the HC group Cable 3 and Fig. 2. “The Rello value decreased in the right precuneus, left triangular Inferior frontal gyrus, left middle frontal gyrus, ight opereular inferior frontal gyrus, left orbital inferior frontal gyrus, left supramarginal gyrus, left angular gyrus, lft inferior temporal gyrus, and right cerebelum,7b, bot increased in the left precentral gyrus and lef fusiform gyrus, inthe [PD-CI group compared with the PD-NC group (Table 4 and Fis. 2). 4.3. Correlation between Reto alteration and MoCA scores ‘The Reto valuein the right precuneus, left triangular inferior frontal Demographic and sina characteristics ofl participants PDClgwpn PONCE CRP 8 19) 2 wane Sexo Toe 78 Be oar get) c6501585 s5s0isa 6150=679 O00! Deewe dentin 620.60) SoNLQaH) = bo ‘en Hey sage 250030 — 2020,30) > on Neca taouss, 275060," irsas0, nao m3) 235) Be) ents wid PD-Cl and both Hs sd patients wilh PD.NG in terms f age (P — 22001, Bonferroni eorection). * Wilco rank-sum tet ula Walls tex MOA scores showed signifeant diflerences when comparing patents with PDI veesus ellen with PD-NC, and paints with PD-Ct verss HOS (P= 0.000), arsine ets 747 (2021) 198672 fyrus, left middle frontal gyrus, right opercular inferior frontal gyrus, left orbital inferior frontal gyrus, left supramarginal gyrus, left angular syrus, lft inferior temporal yrus, and right cerebelum. 7b correlated Positively with MoCA scores the correlation coefficient was 0.712, 8.677,0.691, 0.773, 0.578, 0.712, 0.535, 0.591, and 0.552, respectively The Rel value in the left precentral gyrus and let fusiform gyrus negatively correlated with MoCA scores the coreation coefficient was 0.759 and -0.772, respectively Pg. 4, Discussion The pathophysiological mechanisms of PD-celated i have not been elucidated, andthe treatment methods are limited. Aging is one of the ris factors for PD-MCI{10). Aging is also the strongest predictive factor for PDD(11].A recent study confirmed that aging had a great influence ‘on the cognitive performance of patients with PDL2]. The present study ows hat patients with PD-Cl were older compared with he other (wo groups, which was consistent with previous findings, suggesting that sang oul forte agave pt wh F wih cops el, ‘The DMN comprising partial bran regions is active in the re state but inactive when performing tass[19), The DMN is deemed tobe involved in advanced cognitive functions, including the medial pre- ‘frontal cortex, posterior cingulate cortex, precuncus,infevior parietal lobe, and temporal cortex{4]. The present study found that the Reto values in the precuneus, temporal lobe, medial prefrontal cortex and inferior parietal lobe decreased inthe PD-CI group compared with the PD-NC group; these brain regions positively correlated with MoCA scores, androne etal, revesled the functional disruption ofthe DMN in patien’s with PD before the impairment of cognitionLiS]. This study Showed that the activity in the left medial prefrontal cortex and eft temporal cortex increased in the PD-NC group compared with the HC group, asa cognitive compensation mechanism before the appearance of cognitive decline symptoms. While the Retlo value decreased in the above brain rgions in patients with PD-Ct group compared with the PD-NC group. Moreover, Using ReHo analysis, Lita. revealed that the Reo value increased in the precuneus in patents with PD-MCI compared with HCs; the ReHo value significantly negatively come- lated with the MoCA seore inpatients with PD, indicating tha te local activities increased in che precuneus to improve its function 50 a5 10 compensate for moderate cognitive decline and maintain general cognition in patients with PD-MCI{s]. However, che present study shovied a decreased ReHo value in the precuneus in some patients who met PDD diagnostic criteria a decrease in the Reto value was consid- «red tobe the Functional decompensation of the precuneus. To sum up, is belleved that cognitive decline in patients with PD was related to functional abnormalities in the DMN, and the DMN was affected before Cand continuously deteriorated with disease progression, “This study showed that the Reto value decreased in the cortex ‘elated to visual network Qeft lingual gyrus) in PD patents. The findings suggested thatthe visual network of patients with PD was damaged, indicating that the visual information integration pathway was also involved inthe occurrence of cognitive impairment. Wiliams-Grey etal ddemoastrated an increased risk of progression to dementia in patientsarsine ets 747 (2021) 198672 Fig. 1. aria ceglons showing diferent Rell values between the POC and HC groupe (ot clos indeste a sigalcant increase ia Reto values, Cold colors indleae a sigaifcant decrease ln Reto values) ‘ables ran eplone showing diferent Rett values between the PD-NC and HC groupe akc en a TT ‘with visuospatial and memory deficits (posterior cortical defets{161. Moreover, some scholars found that the PD-MCI and PD-NC groups showed reduced spontaneous brain activity in the occipital cortex (ale carine and cuneate convolution) compared with the HC groupl!7), Besides, Yetkin etal. showed thatthe local atvities in brain regions, including the fusiform gyrus, were abnormal and related to cognitive funeton{ 1). This study foune thatthe Reo value in the left fusiform syrus participating in the visual network increased and negatively Correlated withthe MoCA score inpatients with PD. This was probably because of cognitive compensation by enhancing the efficiency of visual information transmission. Therefore, this stidy proved thatthe decine inthe cognitive function of patients with PD was related to impaired visual pathways. From the perspective of neurotransmitters, previous studies confirmed that patients with PD-CI had dual pathogenesis and the spatial distribution of neurological dysfunction. On the one hand, the dopaminergic dysfunctions of the frontal-sriatum pathway had sreater impact on patients with PD-MCI, involving mainly planning, ‘working, memory, and executive function; on the other hand, the cholinergic disorders in the posterior cortex and temporal lobe more alfectedvisual-spatil function and semantie fuency, and even had a close relationship with the rapid decline in patients with PDD(19) This study found the reduced focal activites in the frontal and temporal lobes whose ReHfo values positively correlated sith MCA seores in patients with PD; also, pat of the posterior cortex regional activity reduced. ¢ was speculated that the dopaminergic and cholinergic disorders jointly participated inthe process of cognitive decline inpatients with PD. In addition, this study showed thatthe right supplementary motor area had a reduced ReHlo value in patients with PD-Cl. Previous studies also confirmed that supplementary motor areas were zssocated with PD-Cl 20]. Some scholars proposed thatthe noradrenergic system from the locus coeruleus could be projected tothe key areas of exceutive func- tions, response inhibition, working memory, and speech fluency, Including the frontal inferior gyrus, supplementary motor ares, dors lateral prefrontal cortex, and anterior eingulate cortex. Specialy, the right frontal inferior gyrus and supplementary motor area, both related to response suppression and attention processing, were regulated by the noradrenergic system]. A research found that the selective norad- renergle reuptake inhibitor atomoxetine not only inereased the fune- onal connectivity Between the right inferior frontal gyrus and dorsal ig. 2 srla regions showing diferent Reto values between the PO-NC and HC groupe (ot clos indicate a signicant Increase in Reto values, Cold colors Indleae a aigafcant decrease ln Reto values)anterior cingulate cortex in PD, These two regions support the executive function of attentional control and inhibition. Atomoxetine also increased the connectivity between the inferior frontal gyrus snd dorsolateral prefrontal cortex, in proportion to the change in executive function (indexed by verbal fuency)(21]. The results of this study further proved that cognitive function inpatients with PD was related to ‘not only the dopaminergic and cholinergic system but also the norad= energie system, “The cortex-thalamus-cerebellar circuit is involved in higher levels of cognitive activites, and the activation ofthe cerebellar circuits related to high-level language, working memory, and spatial processing tasks 2). This study also observed a reduced Rello value in the right cer- belum. 7b in the PD-CI group compared with the PD-NC group and found the PD-C! and PD-NC groups respectively showed reduced spon- taneous brain activity in the left thalamus and right cerebellum.6 ‘compared with the HC group. Harington etal. thought thatthe reduced ReHlo value in the right cerebelium might be related to poor visual ‘organizational function and produce interfering signals and/or eesul- ted in functional separation in the eerebellar-cortial cieuit that regu- lated higher cognitive funetion. However, they also found that the increased amplitude of low-‘requency fluctuation (ALF) in the left ‘cerebellum was associated with poor visual groups. Thisresult suggested that the increase in ALFE in the posterior cerebellum hada pathological rather than compensatory effect on visual-spatial processing25). The ‘ndings indicated that the information transmission efficiency of the arsine es 747 (2021) 198672 cerebellum-thalamus-cortex loop was reduced and involved in the cognitive decline proces in patents with PD, Tn addition, the precentral gyrus, the primary motor arce, is responsible forthe planning, initiation, and execution of an exercise “This study found that the ReHYo value increased in the left precental syrusia patients with PD-CI, implying that it cou be used for cognitive compensation as a brain region adjacent to the lft Fontal lobe whose Spontaneous ativity was reduced. Interestingly, the stdy also showed "atthe dffecentia! bein zegions inthe PD-Cl group compared with the PD-NC group were mostly located in the left hemisphere, The left and ‘ight hemispheres of the brain show significant functional diferences, indicating laterality in brain functions, The lft hemisphere is dominant in anguage and visual processng|2). The results further proved that the right-handed dominant hemisphere, that is, the left hemisphere had a greater degre of activation. “This study had some limitations. First, some patients with PD in this study received dopamine treatment, and the dose of levodopa was not ‘used as a covariate, Therefore, the effect of the drug could not be eliminated. Second, exploration and analysis were not performed in differen cognisive ares. Finally, the sample size shouldbe inreased in future studies fr in-depth exploration In conclusion, the present study indicated thae cognitive decline in patients with PD was associated with aging, abnormal spontaneous foherence both in the DMN and the visual network, midtiple neuro- transmitters and the cerebellum-thalamus-cortex loop, Therefore, the Rello abnormality patterns may help explore the neuropathological ‘mechanisms of Cand also provide a novel insight ito the diagnosis and linia treatment of PDC [Ethical approval All procedures performed in the studies involving human partici ‘pants were in accordance with the ethical standards of Hebei General Hospital and/or national research committee and with the 1964 He! sink! Declaration and ite later amendments or comparable ethical standards, Informed consent Informed consent was obtained from all individual participants included in the study. Founding information ‘This study was funded by Hebei Health Commission, China (Grant number 20200716) Fig . selaceglons showing diferent Het values between the POE and PDANG groups (ot clos indicate a sigalfcatInreae into values. Cold colors ince a sgn 5 decease In Heo values)Nee Lees 747 (2021) 138672 a, ey ¢ i i 3 7 al ! Ll f : H i i 3 | earncom ° 3B ew 5 EF s Ey 6 2 3% w ay 3 f a : i, . i, . OE 3 3 i 5 3 i a 2° Gd. og ¢ eg]: 2 AE ‘ a J fr-nssrcum 4 fess sam 4 cos ct k re ny Soa Ee. Fig. 4. Pearson correlations Betwsen ReHo vals sod MOCA score inpatients with PD, ‘Note: The rai regions trom (2) represented the ght prcunets, left angular inferior frontal gyrus, et mide rocl yeu, right opercular inferior fonal yrs, let orbital inferior frontal gyrus, left supamarginal gyros, left angular gyrus, let infesior temporal gyrus, and eight crebchun To; Reto vals positively corlated with MoCA scores, The regions from (8 represented the lft precentral gyrus and let fusiform gyrus, Reto values neacvely corzelated wit MoCA sores ‘cRediT authorship contribution statement ‘Weina Guot Conceptuslization, Methodology, Softwaze,Investiga- tion, Writing - original draft. Wei Jin: Validation, Formal analysis, ‘Visualization, Software, Na Li: Resources, Writing - review & editing, ‘Supervision, Data curation. Junshu Gao: Resources, Writing - review & ‘editing, Supervision, Data curation, Jiuxwe Wang: Data curation, Formal analysis, Investigation. Yajun Chang: Data curation, Formal analysis, Investigation. Kuochang Vin: Data curation, Formal analysis, Investigation. Yingmin Chen: Methodology, Supervision, Validation. ‘Shugian Zhang: Supervision, Validation. Tianjun Wang: Writing -re- view & editing. Declaration of Competing Interest "The authors declare that they have no confit of interest. ‘Acknowledgments ‘We thank MedSei (svw.medsciediting.com) for English language cditng