RNT Pensamento Negativo Repetitivo Amiloide Tau e Declínio Cognitivo Artigo Científico

Received 14 January 2020 Revised 25 March 2020 Accepted 18 April 2020 DOI 101002alz12116 F E AT U R E D A R T I C L E Repetitive negative thinking is associated with amyloid tau and cognitive decline Natalie L Marchant1 Lise R Lovland1 Rebecca Jones1 Alexa Pichet Binette23 Julie Gonneaud23 Eider M ArenazaUrquijo45 Gael Chételat4 Sylvia Villeneuve23 for the PREVENTAD Research Group 1Division of Psychiatry University College London London United Kingdom 2Studies on Prevention of Alzheimers Disease StOPAD Centre Douglas Mental Health University Institute Montreal Quebec Canada 3McGill Integrated Program in Neuroscience McGill University Montreal Quebec Canada 4Normandie Univ UNICAEN INSERM U1237 PhIND Physiopathology and Imaging of Neurological Disorders Cyceron Caen 14000 France 5Barcelona𝛽eta Brain Research Center Pasqual Maragall Foundation Barcelona Spain Correspondence NatalieLMarchantDivisionofPsychiatry6th FloorMapleHouse149TottenhamCourtRoad University CollegeLondonLondonW1T7NF UK Emailnmarchantuclacuk GaelChételatandSylviaVilleneuvehavecon tributedequallytothework Abstract IntroductionTheCognitiveDebt hypothesisproposesthat repetitivenegativethinking RNT a modifiable process common to many psychological risk factors for Alzheimers disease AD may itself increase risk We sought to empirically examine relationships between RNT and markers of AD compared with anxiety and depression symptoms Methods Two hundred and ninetytwo older adults with longitudinal cognitive assess ments including 113 with amyloidpositron emission tomography PET and tauPET scans from the PREVENTAD cohort and 68 adults with amyloidPET scans from the IMAP cohort were included All participants completed RNT anxiety and depression questionnaires Results RNT was associated with decline in global cognition P 02 immediate P 03 and delayed memory P 04 and global amyloid PREVENTAD P 01 IMAP P 03 and entorhinal tau P 02 deposition Relationships remained after adjusting for potential confounders Discussion RNT was associated with decline in cognitive domains affected early in AD and with neuroimaging AD biomarkers Future research could investigate whether modifying RNT reduces AD risk K E Y W O R D S Alzheimers disease amyloid cognition depression repetitive negative thinking rumination tau worry 1 INTRODUCTION Alzheimers disease AD is a progressive neurological disease In early stages AD is characterized by the aggregation of amyloid beta A𝛽 and hyperphosphorylated tau proteins in the brain1 and worsening memory23 In the absence of diseasemodifying treatments there is an urgent need to identify modifiable risk factors that are associ ated with these biomarkers which can be targeted to prevent future AD This is an open access article under the terms of the Creative Commons AttributionNonCommercial License which permits use distribution and reproduction in any medium provided the original work is properly cited and is not used for commercial purposes c 2020 The Authors Alzheimers Dementia published by Wiley Periodicals LLC on behalf of Alzheimers Association In recent decades a number of psychological risk factors for cogni tive decline and AD have been identified4 These include depression57 and anxiety810 While these risks have generally been considered inde pendently the Cognitive Debt hypothesis suggests that a mechanism frequently present in these psychological risk factorsrepetitive neg ative thinking RNT11may underlie the risk associated with each factor4 Repetitive negative thinking also termed perseverative cog nition is a behaviorally measurable cognitive process that 1054 wileyonlinelibrarycomjournalalz Alzheimers Dement 20201610541064 MARCHANT ET AL 1055 encompasses future worry and past rumination directed thoughts12 and describes the thought process rather than its time ori entation or content It is relatively stable13 but like other traits can also be modified through intervention1415 While RNT is a comparatively new term its components rumination and worry have been associated with memory and executive function in diverse populations1622 The behavioral evidence we suggest implicates RNT as a potential com mon pathway that contributes to increasing AD risk RNTs relationship with neurobiological AD markers amyloid and tau has not yet been empirically examined however memoryrelated worries have been associated with higher amyloid burden in individuals with subjective cognitive decline2324 The current study sought to examine the rela tionship between 1 RNT and longitudinal cognitive change and 2 RNT and AD pathologies using neuroimaging markers of A𝛽 and tau compared to the relationships between symptoms of depression and anxiety and these markers 2 METHODS AND MATERIALS 21 Participants 211 PREVENTAD cohort Two hundred and ninetytwo cognitively normal participants from the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimers Disease PREVENTAD cohort see supporting informa tion provided data for the longitudinal cognitive analyses a subset of whom had undergone A𝛽 and tau positron emission tomography PET scans N 113 Table 1 All participants were aged 55 or older in good physical and cog nitive health had a parent or at least two siblings with past or cur rent AD dementia and were apolipoprotein E APOE genotyped Detailed medical examinations were undertaken by research nurses before enrolment to ensure eligibility for study participation Par ticipants must have completed a measure of RNT to be included in analyses 212 IMAP cohort Data from 68 adults that were either cognitively healthy or with subjective cognitive decline from the MultiModal Neuroimaging in Alzheimers Disease IMAP study were used in the A𝛽 neuroimag ing replication study Table 1 Cognitively healthy participants were recruited from the general population and those with subjective cog nitive decline were recruited from local memory clinics see Perrotin et al25 for details All performed in the normal range in neuropsycho logical tests had no clinical evidence of major neurological or psychi atric disorder had a MiniMental State Examination MMSE 28 and were APOE genotyped Participants must have completed a measure of RNT and undergone an A𝛽PET scan to be included in the analyses HIGHLIGHTS Psychological risks for Alzheimers disease AD often involve repetitive negative thinking RNT The Cognitive Debt hypothesis proposed that RNT itself may increase risk of AD RNT is associated with amyloid and tau deposition in non demented adults RNT predicts decline in cognitive domains affected early in AD Empirical evidence supports RNT as a marker of increased AD risk RESEARCH IN CONTEXT 1 Systematic review We reviewed the literature using traditional sources eg PubMed and GoogleScholar Although the associations between psychiatric symptoms such as depression and anxiety and markers of AD risk are increasingly studied investigation of a thinking style that may be central to these associations has been largely neglected 2 Interpretation Our results suggest that RNT is associ ated with cognitive and neuropathological markers of AD Importantly these are the first data to provide proofof principle support for the Cognitive Debt hypothesis that RNT is an important marker of dementia risk 3 Future directions These findings call for experimental interventions to determine a the causal relationship between RNT and AD biomarkers and b whether reduc ing RNT impacts risk of developing AD 22 Standard protocol approvals registrations and patient consents PREVENTAD was approved by the Institutional Review Board of the McGill University Faculty of Medicine and conducted in accordance with the World Medical Association Declaration of Helsinki Partici pants provided written consent before participation IMAP Caen France was approved by the regional ethics com mittee Comité de Protection des Personnes NordOuest III and is registered with ClinicalTrialsgov number NCT01638949 All partic ipants gave written informed consent before the examinations 15525279 2020 7 Downloaded from httpsalzjournalsonlinelibrarywileycomdoi101002alz12116 by CAPES Wiley Online Library on 30072023 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1056 MARCHANT ET AL TABLE 1 Demographic clinical and biological characteristics of the PREVENTAD and IMAP cohorts PREVENTAD cohort Variable Cognitive Trajectory Substudy N 292 Neuroimaging Substudy N 113 IMAP cohort N 68 Demographics Age years 623 49 675 5 676 94 Sex female n 212 73 85 75 33 49 Educationyears 1539 34 1507 32 129 37 APOE ɛ4 n 114 39 45 40 16 24 MMSE 2884 12 2896 11 MoCA 2807 15 Psychiatric symptoms GAI anxiety score 286 43 20 36 GDS depression score 163 22 128 19 STAIB anxiety score 3676 80 MADRS depression score 159 22 Neuroimaging AD markers Global A𝛽 18FNAV4694 SUVR 132 03 Global A𝛽 18FAV45 SUVR 094 02 A𝛽 a 18 95 12 56 Entorhinal cortex tau 18FAV1451 SUVR 108 01 Inferior temporal cortex tau 18FAV1451 SUVR 116 01 RNT PTQ closest to PET scan 1642 96 194 109 PTQ 1st administration 170 105 168 95 Data are presented as mean standard deviation of participants unless otherwise indicated Abbreviations A𝛽 amyloid beta APOE apolipoprotein E GAI Geriatric Anxiety Inventory GDS Geriatric Depression Scale IMAP MultiModal Neu roimaging in Alzheimers Disease MADRS MontgomeryAsberg Depression Rating Scale MMSE MiniMental State Examination MoCA Montreal Cog nitive Assessment PREVENTAD Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimers Disease PTQ Perseverative Thinking Questionnaire RNT repetitive negative thinking STAIB StateTrait Anxiety Inventory part B SUVR standard uptake volume ratio aA𝛽 positivity was determined using cohort specific cutoffs see supporting information for detail 23 Behavioral measures 231 Repetitive negative thinking The 15item selfreport Perseverative Thinking Questionnaire PTQ26 was used in PREVENTAD and IMAP either in the original English form or translated into French by native speakers Participants respond to questions about how they typically think about negative experiences using Likert scales that range from 0 never to 4 almost always All items are positively scored and higher scores reflect higher levels of RNT Total scores range from 0 to 60 The PTQ was designed to mea sure contentindependent levels of RNT and has been validated for use in both clinical and nonclinical populations26 232 Depression PREVENTAD Participants completed the 15item Geriatric Depression Scale GDS which screens for depressive symptoms in older adults and has a max imum total score of 1527 IMAP Participants completed the Montgomery and Asberg Depression Rat ing Scale MADRS a 10item semistructured interview that measures depressive symptoms It has a maximum total score of 6028 and corre lates highly with the GDS29 233 Anxiety PREVENTAD Participants completed the 20item Geriatric Anxiety Inven tory GAI selfreport questionnaire which screens for anxi ety symptoms in older adults and has a maximum total score of 2030 IMAP Participants completed the trait subscale of the StateTrait Anxiety Inventory STAIB a 20item selfreport questionnaire that assesses habitual anxiety tendencies Scores range from 20 to 8031 and corre late with the GAI30 15525279 2020 7 Downloaded from httpsalzjournalsonlinelibrarywileycomdoi101002alz12116 by CAPES Wiley Online Library on 30072023 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License MARCHANT ET AL 1057 234 Cognition The MMSE and the Montreal Cognitive Assessment MoCA are screening tools for assessing global cognitive function in older adults The MMSE was completed by participants in PREVENTAD and IMAP who underwent neuroimaging scans and the MoCA was completed by the PREVENTAD participants at enrolment who completed cognitive tests PREVENTAD The Repeatable Battery for Assessment of Neuropsychological Sta tus RBANS32 was used to measure cognitive performance The RBANS consists of 12 cognitive tests which yield a global score and five domainspecific index scores immediate memory delayed memory attention spatial cognition and language All measures are standardized with a mean score of 100 and standard devia tion of 15 see Randolph et al 32 for details Cognitive perfor mance was measured at 12month intervals for up to 48 months using different test versions at each time point to minimize practice effects 24 Image acquisition and processing PREVENTAD Participants underwent PET imaging using 18FNAV4694 to assess A𝛽 burden and 18FAV1451 to assess tau burden T1weighted mag netic resonance imaging MRI from an MPRAGE sequence were used to assist with PET processing see supporting information for detailed procedures Briefly for both A𝛽 and tau scans the mean standardized uptake value ratio SUVR for each participant was extracted across both hemispheres from the cortical DesikanKilliany regions A global neocortical A𝛽 index value was calculated by tak ing the mean SUVR in typical AD signature regions33 namely medial and lateral regions in the frontal parietal and temporal lobes The inferior temporal and entorhinal cortical regions were selected as regions of interest ROIs for tauPET analyses because of autopsy and imaging evidence for early pathological deposition in these regions and sensitivity to differentiate impaired versus nonimpaired individuals3435 IMAP The procedures for imaging data handling transformation and determination of amyloid positivity are similar to those used in36 and described in the supporting information Briefly 18F AV45florbetapirPET images were corrected for partial volume effects and spatially normalized to generate SUVRs The global neocortical A𝛽 index was obtained in each individual from the florbetapirPET SUVR images using a neocortical mask37 25 Statistical analyses The associations between RNT and potential confounders ie demo graphic characteristics MMSEMoCA symptoms of depression and anxiety were investigated using separate linear regression models with RNT as the outcome APOE status was dichotomized into ɛ4 positive and ɛ4negative In PREVENTAD the assessment of RNT was added to an ongo ing study All participants filled in the questionnaire in Autumn 2016 see supporting information for detailed information about timing of RNT data collection relative to neuroimaging and cognitive assess ments A second measure of RNT was completed 1 year later by 200 68 participants The relative stability of RNT over time was exam inedtoaddresswhetherthecollectiontimeofthefirstRNTassessment in relation to the cognitive assessments would influence temporality assumptions of the study This was done by computing the intraclass correlation coefficient ICC for RNT across the interval between the two RNT measurements We further examined whether change in RNT was associated with amyloid and tau levels using the models described below The relationship between RNT and change in cognition over time was examined using linear mixed effects models which are robust to unbalanced and incomplete data in longitudinal designs38 These mod els allowed for the inclusion of all eligible data points for a given analy sis Missing data in PREVENTAD reflect in large part the ongoing study recruitment ie followup visits have yet to be conducted rather than participant dropout Logistic regression analyses showed no associa tions with any variable and missing data across time points and that only sex was associated with missing data at individual time points Sex was included as a covariate in the models along with other potentially confounding variables Separate models were fitted for each of the six raw composite scores from the RBANS global cognition immediate memory delayed memory attention visuospatial cognition and language with fixed effects of RNT time 0 12 24 36 and 48 months and the interaction between RNT and time as the main explanatory variables Similar mod els were fitted with either depression or anxiety and their respective interactions with time as the main explanatory variable and cognitive scores as the outcome All models included fixed effects of sex age at enrolment educational level APOE status and their interactions with time as covariates permitting both absolute values of the cognitive outcomesand their trajectoriesover time tovaryaccording todifferent valuesofthesemeasuresArandomeffectofindividualwasspecifiedto account for repeated measures on participants over time An unstruc tured residual covariance matrix allowed the residual variation at each time point and the covariances between pairs of time points to remain unconstrained Models were estimated using restricted maximum like lihood Linearity checks were performed and where there was evi dence of departure from linearity quadratic terms were included in the model Unadjusted linear regressions were used to examine the relation ships among RNT A𝛽 and tau Log10 transformed global A𝛽 index 15525279 2020 7 Downloaded from httpsalzjournalsonlinelibrarywileycomdoi101002alz12116 by CAPES Wiley Online Library on 30072023 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1058 MARCHANT ET AL or tau entorhinal or inferior temporal values were specified as the outcome variable in each model with RNT as the exposure Similar models were fitted with depression or anxiety as the exposure Where evidence of an association was observed an adjusted model was constructed by adding known predictors of A𝛽 as covariates age APOE status cognitive function measured using MMSE39 3 RESULTS Baseline RNT was not associated with age MMSE MoCA education or APOE status in either cohort all P 05 however it was associated with sex in the PREVENTAD cohort with women showing higher lev els unstandardized 𝛽 344 95 confidence interval CI 076 to 617 P 012 female mean 1797 standard deviation SD 1063 male mean 1454 SD 96 RNT was positively associated with depres sive symptoms PREVENTAD unstandardized 𝛽 206 95 CI 156 to 256 P 001 IMAP unstandardized 𝛽 146 95 CI 031 to 261 P 01 and anxiety symptoms PREVENTAD unstandardized 𝛽 132 95 CI 109 to 156 P 001 IMAP unstandardized 𝛽 079 95 CI 052 to 106 P 001 Stability measures of RNT measured at a 1year interval returned an ICC of 075 95 CI 069 to 08 consid ered to show good reliability40 indicating that scores were relatively stable 31 Cognitive decline PREVENTAD Of the total sample cognitive data were available for 288 986 participants at baseline 242 829 at 12 months 150 514 at 24 months 101 346 at 36 months and 45 154 at 48 months Eleven participants withdrew after baseline one participant withdrew after the 12month visit and one participant was excluded after the 24 month visit total withdrawalexclusion 44 the remainder were yet to complete followup visits Because we found strong evidence of an acceleration in decline over time for immediate memory and a deceler ation for language we opted to retain quadratic terms for time in mod els for all six cognitive scores We found evidence of a faster decline in cognitionovertimewithgreaterRNTTable2andFigure1Globalcog nitiondeclined 040 pointsper year more quicklyfor each1 SD increase on the PTQ scale standardized 𝛽 040 95 CI 074 to 005 P 02 Similar differences in rate of change per additional SD increase on the PTQ scale were observed for both immediate memory standard ized 𝛽 062 95 CI 116 to 008 P 03 and delayed memory standardized 𝛽 047 95 CI 093 to 002 P 04 There was weak evidence for a negative association with language standardized 𝛽 040 95 CI 084 to 005 P 08 and no evidence of any dif ference in rate of change for attention or visuospatial cognition and likewise little evidence of an association between overall levels of cog nition and RNT all P 05 We found evidence of a faster decline of global cognition with greater depression symptoms standardized 𝛽 046 95 CI 082 to 009 P 01 and weak evidence for decline in immediate memory standardized 𝛽 055 95 CI 112 to 003 P 06 and delayed memory standardized 𝛽 041 95 CI 089 to 007 P 09 We also found evidence of a faster decline of global cognition with greater anxiety symptoms standardized 𝛽 034 95 CI 068 to 000 P 05 and delayed memory standardized 𝛽 057 95 CI 100 to 014 P 009 32 Amyloid PREVENTAD and IMAP We found evidence of a positive relationship between RNT and A𝛽 in the PREVENTAD cohort with higher RNT associated with greater A𝛽 deposition This finding was replicated in the IMAP cohort By contrast no evidence of a relationship between depression or anxiety symptoms and A𝛽 were found in either cohort Table 3 PREVENTAD In the unadjusted model RNT was associated with global A𝛽 stan dardized 𝛽 023 95 CI 005 to 041 P 014 and this rela tionship was still evident after adjustment for age APOE status and cognitive function standardized 𝛽 019 95 CI 001 to 038 P 04 Figure S1a in supporting information In the subset of participants who completed the PTQ twice an increase in RNT was weakly associated with lower global A𝛽 in the unadjusted model N 89 standardized 𝛽 020 95 CI 040 to 001 P 06 and signifi cantly associated with lower global A𝛽 in the adjusted model N 88 standardized 𝛽 028 95 CI 048 to 009 P 004 IMAP In the unadjusted model RNT was associated with global A𝛽 standard ized 𝛽 026 95 CI 002 to 049 P 03 and this relationship like wise remained in the model adjusted for age APOE status and cog nitive function standardized 𝛽 024 95 CI 002 to 047 P 03 Figure S1b Further adjustment for cognitive status healthy vs sub jective cognitive decline SCD did not affect the results standard ized 𝛽 025 95 CI 002 to 047 P 03 Adjusting for the time lag between RNT and neuroimaging assessments in participants with these data available slightly reduced the association standardized 𝛽 022 95 CI 003 to 047 P 08 33 Tau PREVENTAD We found evidence of a positive association between RNT and tau deposition in the entorhinal but not inferior temporal cortex with higher RNT associated with greater tau deposition We found no evi denceofarelationshipbetweeneitherdepressiveoranxietysymptoms 15525279 2020 7 Downloaded from httpsalzjournalsonlinelibrarywileycomdoi101002alz12116 by CAPES Wiley Online Library on 30072023 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License MARCHANT ET AL 1059 TABLE 2 Crosssectional and longitudinal relationships between a RNT and cognition b depressive symptoms and cognition c anxiety symptoms and cognition Global Cognition Immediate Memory Delayed Memory Attention Spatial cognition Language Variable Est 95 CI P Est 95 CI P Est 95 CI P Est 95 CI P Est 95 CI P Est 95 CI P a RNT RNT 005 103 to 094 93 024 092 to 139 69 052 033 to 137 23 158 322 to 005 06 023 116 to 161 75 036 063 to 135 48 Time 149 294 to 592 51 225 476 to 926 53 621 041 to 1201 04 140 550 to 831 69 492 1247 to 263 20 234 336 to 804 42 Time2 010 042 to 022 54 082 125 to 039 001 060 096 to 024 001 027 069 to 016 22 032 019 to 083 22 099 063 to 135 001 RNT Time 040 074 to 005 02 062 116 to 008 03 047 093 to 002 04 008 062 to 045 77 003 060 to 055 93 040 084 to 005 08 b Depressive symptoms Depression symptoms 009 089 to 107 85 005 120 to 109 93 036 050 to 121 41 045 208 to 118 59 017 121 to 155 81 034 065 to 133 50 Time 152 286 to 590 50 283 424 to 990 43 658 070 to 1245 03 140 558 to 839 69 475 1231 to 282 22 235 354 to 823 43 Time2 013 046 to 019 42 087 131 to 044 001 063 099 to 027 001 028 071 to 014 19 031 020 to 083 23 099 063 to 136 001 Depression symptoms Time 046 082 to 009 01 055 112 to 003 06 041 089 to 007 09 016 073 to 041 57 011 072 to 050 73 018 066 to 030 47 c Anxiety symptoms Anxiety symptoms 033 064 to 130 50 017 130 to 096 77 076 007 to 159 07 046 209 to 116 58 045 091 to 182 51 050 047 to 147 31 Time 117 337 to 571 61 248 457 to 953 49 608 033 to 1184 04 154 541 to 849 66 490 1243 to 264 20 215 370 to 801 47 Time2 012 043 to 020 47 084 127 to 041 001 060 096 to 025 001 027 070 to 015 21 032 019 to 083 22 10 064 to 136 001 Anxiety symptoms Time 034 068 to 000 05 041 093 to 011 12 057 100 to 014 009 029 023 to 080 27 020 075 to 035 47 024 067 to 020 29 All estimates are adjusted for age sex education and APOE status Note All estimates apart from time are standardized Time indicates year Participants N 292 Observations N 826 Abbreviations APOE apolipoprotein E CI confidence interval RNT repetitive negative thinking 15525279 2020 7 Downloaded from httpsalzjournalsonlinelibrarywileycomdoi101002alz12116 by CAPES Wiley Online Library on 30072023 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1060 MARCHANT ET AL 100 102 104 106 108 Global cognition 0 12 24 36 48 100 102 104 106 108 Immediate memory 0 12 24 36 48 100 102 104 106 108 Delayed memory 0 12 24 36 48 Time months RNT 7 RNT 17 RNT 27 FIGURE 1 Predicted cognitive scores over time for participants with repetitive negative thinking RNT scores of 7 17 and 27 on the Perseverative Thinking Questionnaire PTQ approximating 1 standard deviation SD mean and 1 SD RNT scores in our sample Estimates are for a female participant aged 625 years at entry to the study with some undergraduate education and no APOE 𝜀4 allele from the PREVENTAD cohort Note Education was converted into categories to avoid curvature adjustments for this variable 1 Elementary to high school 2 some undergraduate 3 some postgraduate and 4 postgraduate where some indicates that the course was started but not completed and either measure of tau Table 3 In the unadjusted model RNT was associated with entorhinal tau standardized 𝛽 023 95 CI 005 to 041 P 02 and evidence of this relationship remained in the model adjusted for age APOE status and cognitive function standardized 𝛽 019 95 CI 001 to 037 P 04 Figure S1c In the subset of partic ipants who completed the PTQ twice an increase in RNT was not asso ciated with entorhinal or inferior temporal cortical tau in unadjusted or adjusted models all P 05 4 DISCUSSION The current study sought to empirically test the Cognitive Debt hypothesis by investigating in cognitively intact older adults the rela tionship between RNT and markers of AD cognitive decline and neu roimaging measures of A𝛽 and tau We found that higher levels of RNT were associated with more rapid decline in global cognition immedi ate and delayed memory over a 48month period Further RNT was associated with higher levels of tau in the entorhinal cortex a region of early aggregation and with global brain amyloid in two independent cohorts While we found evidence of associations between depression and anxiety symptoms and cognitive change RNT was the only predic tor consistently associated with decline in multiple ADrelated cogni tive domains We found no evidence for any relationship between anx iety and depression with neuroimaging AD biomarkers While cognitive impairment in preclinical AD can be spread across cognitive domains2 two consistent and strong predictors of progres sion to AD are deficits in episodic memory and global cognition24142 The findings from our study show a relationship between RNT and decline in these specific cognitive domains supporting the proposal that RNT is associated with AD risk These findings also build on pre vious work showing worse cognitive performance in adults with high rumination18 and worry21 and extend them to focus on domains spe cific to AD namely episodic memory In our study RNT was also associated with global A𝛽 burden in two independent cohorts of cognitively intact adults that used differ ent tracers and processing methods and even after accounting for the known predictors of A𝛽 depositionage APOE ɛ4 status and cognitive function39 RNT was also associated with symptoms of depression and anxiety however neither of these symptoms were themselves associ ated with A𝛽 pathology The inferior temporal and entorhinal cortices have been high lighted as key regions of tau inception and predictors of cognitive impairment based on autopsy data3443 and more recent neuroimaging research3544 With increasing evidence that entorhinal tau deposition occurs early45 and that inferior temporal cortical deposition occurs later in the pathological AD cascade343544 one could argue that RNTs association with entorhinal tau supports its role as an early marker of AD Alternatively or additionally as only relatively young cogni tively intact participants were included in this study they have rela tively low levels of tau Tau deposition may therefore not yet have extended from the entorhinal cortex to the inferior temporal region However this alternative proposal seems unlikely given that age was 15525279 2020 7 Downloaded from httpsalzjournalsonlinelibrarywileycomdoi101002alz12116 by CAPES Wiley Online Library on 30072023 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License MARCHANT ET AL 1061 TABLE 3 Variance in neuroimaging biomarkers of Alzheimers disease AD explained by putative psychological AD risk factors a Amyloid Tau b Amyloid Global A𝜷 18FNAV4694 Entorhinal cortex 18FAV1451 Inferior temporal cortex 18FAV145 Global A𝜷 18FAV45 Variable Standardized Beta 95 CI P Standardized Beta 95 CI P Standardized Beta 95 CI P Variable Standardized Beta 95 CI P Unadjusted models Unadjusted models 1 RNT 023 005 to 041 01 023 005 to 041 02 015 003 to 034 11 1 RNT 026 002 to 049 03 3 Depression symptoms 010 029 to 009 3 01 009 to 028 31 004 015 to 023 69 3 Depression symptoms 02 004 to 044 1 2 Anxiety symptoms 009 009 to 028 32 003 022 to 016 77 001 019 to 018 95 2 Anxiety symptoms 012 012 to 036 33 Adjusted model Adjusted model 1 RNT 019 001 to 038 04 019 001 to 037 04 012 007 to 031 22 1 RNT 024 002 to 047 03 Age 017 002 to 036 09 021 002 to 04 03 019 000 to 039 05 Age 033 010 to 057 007 APOE 026 008 to 044 006 017 001 to 035 06 014 005 to 033 14 APOE 032 009 to 055 007 MMSE 005 014 to 024 58 003 022 to 016 75 002 018 to 022 84 MMSE 008 015 to 032 47 a Predictors of global cortical A𝛽 and regional tau in the PREVENTAD cohort and b predictors of globalA𝛽 in the IMAP cohort replication study Standardized beta values are displayed to allow for direct comparison of each variables contribution Unadjusted models examine RNT anxiety and depressive symptoms as independent explanatory variables in separate models Only RNT explained AD biomarker variance and was therefore retained in the adjusted model The adjusted model included RNT Age APOE status and MMSE and all variables were adjusted for each other Note PREVENTAD participants N 113 for unadjusted amyloid and tau models N 111 for adjusted models IMAP participants N 68 for unadjusted and adjusted models Abbreviations A𝛽 amyloid beta APOE apolipoprotein E CI confidence interval IMAP MultiModal Neuroimaging in Alzheimers Disease MMSE MiniMental State Examination PREVENTAD Pre symptomatic Evaluation of Experimental or Novel Treatments for Alzheimers Disease RNT repetitive negative thinking 15525279 2020 7 Downloaded from httpsalzjournalsonlinelibrarywileycomdoi101002alz12116 by CAPES Wiley Online Library on 30072023 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License 1062 MARCHANT ET AL associated with tau deposition in both inferior temporal and entorhinal cortices One explanation for RNTs association with A𝛽 and tau is via the stress pathway Indeed RNT is associated with indicators of stress eg elevated blood pressure cortisol and has been called a behavioral marker of chronic physiological stress46 Evidence from the human animal and cellular literature suggest that stress and glucocorticoids contribute to A𝛽 and tau pathogenesis4749 and risk for AD50 As RNT levels are relatively stable in absence of intervention engaging in this cognitive process may chronically activate the stress response thereby increasing vulnerability to AD This study has some limitations The PREVENTAD cohort was cre ated to study individuals at elevated risk of dementia ie with at least one firstdegree relative with AD therefore the findings from the cur rent study may not be generalizable to a broader population of older adults RNT was assessed at different time points and sometimes retro spective to cognitive testing While RNT levels may have changed over the course of participation and ideally multiple measures of RNT over time preceding the cognitive assessments are needed to assess stabil ity we did show that RNT was relatively stable over a 1year interval Due to the ongoing nature of the PREVENTAD study data were often unavailable for the followup cognitive testing It is important to note that data were largely unavailable due to followup visits not yet being conducted rather than participant dropout therefore were less likely to be influenced by survivor bias However we cannot be sure that the missing data did not bias estimates of magnitude and direction of cog nitive trajectories We tried to mitigate this possibility by using multi level models of longitudinal data and including factors associated with missingness as covariates Further and in line with a widely held view in epidemiology we did not correct for multiple comparisons51 Rather our approach was to transparently report the number of analyses per formed It should be noted that the means and variances in depression and anxiety scores were relatively lower than seen in the RNT mea sure in the cohorts that were examined in this study In a more clin ically diverse population correlations with the depression and anx iety scores may also have been significant Alternatively as depres sion and anxiety were associated with cognitive decline but not amy loid or tau it may be these symptoms are more indicative of age or nonspecific dementiarelated decline whereas RNT may be a more precise marker for AD Indeed a recent systematic review examin ing the relationship between depression and A𝛽 reported equivocal findings52 and a separate review examining depression and tau found no evidence of a relationship53 Far less research has focused on anxi ety however there is a small body of evidence reporting relationships between anxiety and AD biomarkers5455 The relatively high degree of variance in RNT levels in two independent populations indicates that the PTQ may be a useful tool to measure AD risk in nonclinical populations Further replication of these findings along with devel opment of established cutoffs sensitivity specificity and predictive value data must be performed before recommending an RNT question naire as a screen for inclusion of highrisk participants in future clinical trials DespitetheCognitiveDebthypothesisproposalthatRNTincreases risk for AD the opposite may also be true A𝛽 andor tau may aggregate first disrupt neural circuitry which then leads to a difficulty in disen gaging from thoughts and elevated RNT reverse causality If this were the case one might expect that higher levels of amyloid and tau would be associated with increases in RNT however the preliminary results presented here do not support this argument Still this was an obser vational study with relatively few participants meeting criteria for sub stantial amyloid deposition ie A𝛽 positive and no means to assess causality Investigations using data from longitudinal birth cohorts with multiple neuroimaging measures or intervention studies would help address these questions In this first empirical investigation of the Cognitive Debt hypothe sis we find evidence for a relationship between RNT cognitive decline A𝛽 and tau burden in cognitively intact older adults While it is not known whether reducing RNT would reduce risk of AD this is cer tainly an avenue worth exploring Behavioral interventions known to reduce RNT such as talking therapies14 or mindfulness15 could be examined with cognitive andor pathological AD markers as outcomes Ongoing preventative clinical trials targeting the emotional dimension of dementia risk and aging will be able to directly examine these ques tions eg Marchant et al56 ACKNOWLEDGMENTS The authors would like to thank Florence Mézenge Brigitte Landeau Renaud La Joie Audrey Perrotin Alexandre Bejanin Robin de Flo res Clémence Tomadesso Justine Mutlu Nicolas Villain Marine Fou quet Katell Mevel Francis Eustache Béatrice Desgranges Stéphanie Egret Vincent de La Sayette JeanClaude Baron Fausto Viader Alice Pélerin Malo Gaubert Géraldine Poisnel Géraldine Rauchs Anne Quillard Anne Chocat Ahmed Abbas Louisa Barré Alain Man rique Denis Guilloteau Florence Pasquier Serge Belliard Christo pher Rowe Victor Villemagne Antoine Lutz Valentin Ourry Thibaut Anquetil Jacques Dayan Nicolas Delcroix Mona Leblond Alice Pelerin Maxime Quincé Christian Schupp the Cyceron staff members and the volunteers who were included in the PREVENTAD and IMAP studies Natalie L Marchant was supported by a Senior Fellowship from the Alzheimers Society ASSF15b002 Alexa Pichet Binette was sup ported by a joint scholarship from the Alzheimers Society Canada and the Fonds de Recherche du QuébecSanté Sylvia Villeneuve was supported by a Canada Research Chair and a Canada Fund for Inno vation grant The PREVENTAD PET scans were funded by Cana dian Institutes of Health Research foundation grant an Alzheimers Association grant a joint Alzheimer Society of Canada and a Brain Canada Research grant and a Lemaire foundation donation to S Vil leneuve The PREVENTAD cohort was funded by generous support from McGill University the government of Canada an unrestricted gift from Pfizer Canada the Canada Fund for Innovation the Dou glas Hospital Research Centre the Levesque Foundation McGill Uni versity and Genome Quebec Innovation Center The IMAP study was supported by Foundation Plan Alzheimer Alzheimer Plan 2008 2012 Programme Hospitalier de Recherche Clinique PHRCN 2011 15525279 2020 7 Downloaded from httpsalzjournalsonlinelibrarywileycomdoi101002alz12116 by CAPES Wiley Online Library on 30072023 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License MARCHANT ET AL 1063 A0149338 and PHRCN 2012 120060347 Agence Nationale de la Recherche LONGVIE 2007 Région BasseNormandie Association France Alzheimer et maladies apparentées AAP 2013 Data used in preparation of this article were obtained from the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimers Disease PREVENTAD program httpsdouglas researchmcgillcastopadcentre A complete listing of PREVENTAD Research Group can be found in the PREVENTAD database https preventadloriscaacknowledgementsacknowledgementsphpdate 20181217 Funding sources had no role in the design and conduct of the study collection management analysis and interpretation of the data preparation review or approval of the manuscript and the decision to submit the manuscript for publication CONFLICTS OF INTEREST All authors report no conflicts of interest REFERENCES 1 Jack CR Jr Bennett DA Blennow K et al NIAAA research frame work toward a biological definition of Alzheimers disease Alzheimers Dement 201814535562 2 Bäckman L Jones S Berger AK Laukka EJ Small BJ Cognitive impair ment in preclinical Alzheimers disease a metaanalysis Neuropsychol ogy 200519520531 3 Wilson RS Leurgans SE Boyle PA 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and older nondemented adults Am J Geriatr Psychiatry 200917493 502 56 Marchant NL Barnhofer T Klimecki OM et al The SCDWell random ized controlled trial effects of a mindfulnessbased intervention ver sus health education on mental health in patients with subjective cog nitive decline SCD Alzheimers Dement 20184737745 SUPPORTING INFORMATION Additional supporting information may be found online in the Support ing Information section at the end of the article How to cite this article Marchant NL Lovland LR Jones R et al Repetitive negative thinking is associated with amyloid tau and cognitive decline Alzheimers Dement 20201610541064 httpsdoiorg101002alz12116 15525279 2020 7 Downloaded from httpsalzjournalsonlinelibrarywileycomdoi101002alz12116 by CAPES Wiley Online Library on 30072023 See the Terms and Conditions httpsonlinelibrarywileycomtermsandconditions on Wiley Online Library for rules of use OA articles are governed by the applicable Creative Commons License FICHA DE LEITURA PENSAMENTO NEGATIVO REPETITIVO ESTÁ ASSOCIADO A AMILOIDE TAU E DECLÍNIO COGNITIVO Síntese do assunto do artigo A doença de Alzheimer é uma doença neurológica progressiva marcada nos estágios iniciais pela agregação de betaamilóide A e proteínas tau hiperfosforiladas no cérebro e piora da memória A hipótese da Dívida Cognitiva propõe que o pensamento negativo repetitivo RNT um processo modificável comum a muitos fatores de risco psicológico para a doença de Alzheimer DA pode aumentar o risco O presente estudo procurou examinar a relação entre RNT e alteração cognitiva longitudinal e patologias RNT e DA usando marcadores de neuroimagem de Aβ e tau Objetivos da pesquisa Examinar empiricamente as relações entre RNT e marcadores de DA em comparação com sintomas de ansiedade e depressão Procedimentos realizados Duzentos e noventa e dois idosos com avaliação cognitiva longitudinal incluindo 113 com tomografia por emissão de pósitrons amilóide PET e tau PET exames da coorte PREVENTAD e 68 adultos com exames de amiloide PET do A coorte IMAP foi incluída Todos os participantes completaram o questionário sobre RNT pensamento negativo repetitivo ansiedade e depressão Descrição resumida dos resultados RNT foi associado com declínio na cognição global P 002 memória imediata P 003 e memória atrasada P 004 e deposição de amilóide global PREVENTAD P 001 IMAP P 003 e tau entorrinal P 002 As relações permaneceram após o ajuste para possíveis fatores de confusão RNT foi associado com declínio em domínios cognitivos afetados precocemente na DA e com biomarcadores de neuroimagem da doença de Alzheimer Pesquisas futuras poderiam investigar se a modificação do RNT reduz o risco de DA A partir dos resultados percebese que o RNT está associado a marcadores cognitivos e neuropatológicos da DA Declínio cognitivo PREVENTAD foram encontradas fortes evidências de uma aceleração no declínio ao longo do tempo para a memória imediata e uma desaceleração para a linguagem além do declínio mais rápido na cognição ao longo do tempo com maior RNT Amilóide PREVENTAD e IMAP encontramos evidências de uma relação positiva entre RNT e Aβ na coorte PREVENTAD com maior RNT associado a maior deposição de Aβ Tau PREVENTAD evidências de uma associação positiva entre RNT e deposição de tau no córtex entorrinal mas não no córtex temporal inferior com maior RNT associado a maior deposição de tau Não encontramos nenhuma evidência de relação entre sintomas depressivos ou de ansiedade e qualquer medida de tau Conclusões O RNT foi associado ao declínio nos domínios cognitivos afetados no início da e aos biomarcadores de neuroimagem da Pesquisas futuras poderiam investigar se a modificação do RNT reduz o risco de DA Os níveis mais altos de RNT foram associados a um declínio mais rápido na cognição global memória imediata e atrasada em um período de 48 meses A partir dos estudos percebese que há uma relação entre RNT e declínio nesses domínios cognitivos específicos apoiando a proposta de que RNT está associado ao risco de DA Intervenções comportamentais conhecidas por reduzir o RNT como terapias de fala ou mindfulness podem ser examinadas com marcadores de DA cognitivos eou patológicos como resultados Referência do Artigo Marchant NL Lovland LR Jones R Pichet Binette A Gonneaud J Arenaza Urquijo EM Chételat G Villeneuve S PREVENTAD Research Group 07 Julho 2020 Pensamento negativo repetitivo está associado a amiloide tau e declínio cognitivo Alzheimers Dement Acesso em 02 de agosto de 2023 de httpsalzjournalsonlinelibrarywileycomdoi101002alz12116