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    Trajectories of Depressive Symptoms Before Diagnosis of Dementia A 28-Year Follow-Up Study Enhanced Reader

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    CLL fesewch JAMA Psychiatry | Original investigation Trajectories of Depressive Symptoms Before Diagnosis of Dementia A28-Year Follow-up Study ‘Archana Sigh Manoux. PO; Aline Dgravt, MSc: Agnes Four, PRD Jess Abe, PHD aus Ebmoie, MO, PRO; Mila Kiva PhO; Séverne Sabla, PRO IB Estoril page 672 IMPORTANCE Neuropsychiatric symptoms, depressive symptoms in particular, are common gee Inpatients with dementia but whether depressive symptoms in adulthood Increases therisk for dementia remains the subject of debate. [Ey Supplemental content ‘OBIECTIVE To characterize the trajectory of depressive symptoms aver 28 yeas prior ta dementia diagnosis to determine whether depressive symptoms cart isk for dementia DESIG, SETTING. AND PARTICIPANTS Upto 10:308 persons, aged 35 055 years, were recruited to the Whitehall cohort study in 1985, withthe end of follow-up in 2015. Data analysis for this study ina UK general community was conducted from October to December 2016, [EXPOSURES Depressve symptoms assessed on 9 occasions between 1985 and 2072 using the General Health Questionnaire [Malti OUTCOMES AND MEASURES Incidence of dementia(n = 322)between 1985 and 2015 [RESULTS Of the 10189 persons included in the study, 6838 were men (6726) and 3351 were ‘women (33). Those reporting depressive symptoms in 985 (mean fllow-up, 27 years) dd not have significantly increased risk for dementia (hazard ratio [HR], 121; 959% Cl, 095-154) In Cox egression adjusted for sociodemographic covariates, health behaviors, and chronic conditions. However, those with depressive symptoms in 2003 (mean follow-up, 1 years) hha an increased risk (HR, 172: 9556 CI, 121-244). Those with chronicrecuring depressive symptoms (=2 of 3 occasions) inthe early study phase (mean follow-up. 22 years) didnot have excess risk (HR, 102; 953% Cl, 72:4) but those with chronicirecurring symptoms in the late phase (mean follow-up, years) did have higher risk for dementia (HR, 167:95% Cl, 111.249), Analysis of retrospective depressive trajectories over 28 yeas, using mixed models and a backward time scale, shows hatin those with dementis, ifferences in depressive symptoms compared with those without dementia became apparent il years (cfference, (0.61, 9596 Cl,0.08-113: P= 02) before dementia clagnosis and became more than 9 times. larger atthe year of ciagnosis(ifference, 5 81; 95% Cl 481-6 8 P <.001). Auth ations INSERM IOI, CONCLUSIONS ANO RELEVANCE Depresiv symptoms inte ety paseo testy eterna covespondngto midi evenvnencroncecuring donetincease ter fordementa, erent oan ‘ong wihncuranascfderessivtrgectoresover28 years ness restssggesthat ‘ft sy pen depressive sponses poder eset demerit the stare conenon ‘Socneter ac ath ‘causes. The findings do not support the hypothesis that depressive symptoms increase the [ary ayes risk for dementia. —— _ KS Deparorant of Pye. ies Onord Osler Erg Erte Comesponding ute: Archana Sing Maou PHO. INSERM UO, Centre for RevearchinEpideriegy ane opultion Feth Hopia Pa Bouse 8:56 15 Avene Plast Courier 94807 {Au aie 20074 72.78, 101001 eapayetey 20170660, ile ade, Francs Pedorine May 7207 Grctanasingh manooxaivarm (© 2017 American Medical Association. Al rights reserved. —— ‘Tetris Depresve Symptoms Before Dingess of Dementia ‘mentia, isa progressive disorder. The histopatholog cal hallmarks of AD begin decades prior to its clinical cexpression?;a recent study estimated that amyloid-p depos- its form overa period of more than 2 decades.? The long pre- linical phase of dementia has implications forthe timing of interventions. There is growing consensus that interventions should target the earliest possible phase, perhaps the asymp- tomatic stage,* tobe effective. The other major implication, ‘hich has received lessattention to date, isthe analytic frame: ‘workused toidentify putative risk factors for dementia, When ‘measured in the years immediately prior to dementia diagno: sis, these factors are likely to reflect common causes, the ef {ects of preclinical disease (reverse causation), or prodromal ‘changes rather than risk factors for dementia. ‘There isconsiderable research on the association of depres sion or depressive symptoms with dementia. A meta-analysis ‘published in 2006 suggested that depression isassociated with ‘8 2-fold increased risk for AD.® but studies covering the same periodalso concluded that depression may bea prodromal fea ture of dementia, implying no causal effectof depression on dementia, Recent studies using repeat assessments of depres: sive symptoms have shown increasing symptoms tobe associ- ated with the risk for dementia." In these studies, depres- sion trajectories were assessed over 5 years in one study” and ‘over I years in the other study," not ong enough to cover the preclinical phase of dementia. Furthermore, the analyticstrat- egy did not allow depressive symptoms in the follow-up period for dementia to be examined. Thus, whether depres- sion isa risk factor for dementia or a symptom of an underly ing neurodegenerative process could not be determined, The objective of our study isto characterize trajectories, of depressive symptoms stating at dementia diagnosis using aa backward timescale over 28 years and compare them with cchangesin depressive symptoms over the same period in those free fiom dementia. A secondary objectiveistoassess whether ‘dementia risk is higher in those with chronic(recurring de- pressive symptoms in midlife and late life. A= disease (AD), the most common form of de Methods ‘Study Design and Participants. ‘The Whitehall studyisan ongoing cohort study of 10308 per- sons (6895 menand 3413 women), aged 351055 yearsat study recruitment in 1985." Participants responded to question- naireand underwent structured clinical evaluation, consist- ing of measures of anthropometry and cardiovascular and _metabolicrisk actorsand diseases. Follow-upassessment in- ‘cluding postal questionnaire, and clinical examinations have taken place approximately every § years. A postal question: naire-only wave was also undertaken inbetween these waves. Participants provided writen informed consent. Participant consent and research ethies approvals (University College London ethics committee) are renewed at each contact; the latest approval was by the Joint University College London/ University College London Hospitals Committee on the [Bthics of Human Research (Committee Alpha; reference iamoprchis.com ‘rigalnvesigaion Resear KeyPoints ‘Question Does the couse of depressive symptoms over cuhoodin those who devon cement die om those who remain dementia ree? Findings This cohort study fund that depressive symptoms in Iatelifebut ot mile were asoistedithinereasedk for ‘erent analyss of depressive symptoms spannng28 yeas showed ther to emerge approximately a decade pris to erenta dagnoss. No substantive dferencesn depressive symtoms were apparent beteen those who wen onto develop eremia and dementi-free persons 1210 28 yeas prio erentia diagnos, “Meaning. Theasocation between depressive symptoms and erent in older adults may be pimatiy duet common causes or depressive symptomsbeinga featur ofthe precinicl phase of dementia '85/0938). Data analysis for this study was conducted from October to December 2016, Depressive Symptoms Depressive symptoms were elf reported on 9 occasions (1985, 1989, 1991, 1997, 2001, 2003,2006,2007, and 2012) using the 30-item General Health Questionnaire (GHO-30),!* a well- established screening questionnaire for nonpsychotic psycho logical distress, largely depression, suitable for use in general population studies. Response options to 30 questionsare not atall, no more than usual, rather more than usual, and much ‘more than usual. The binary scoring method was used (the 2 Teast symptomaticanswers scoring O and the 2 most sympto- ‘matic answers scoring I), and so the total score ranged from 0 1030, Scores of5 or more defined caseness or the presence of depressive symptoms." Depressive symptoms were also assessed using the 20-item Center for Epidemiologic Studies Depression Scale (CES-D)* on 3 occasions (2003, 2007, and 2012). The CES-Disa20-item inventory ofthe National Insti= tute of Mental Health Center for Epidemiological Studies to assess the frequency and severity of depressive symptoms using standard cutofT score of 16 or greater, Relative perfor- ‘mances within the cohort of GH0-30 and CES-D against the interviewer-administered revised Clinical Interview Sched ule as criterion for detecting a depressive episode were simi Jar; sensitivity and specificity were 78% and 83% for the GHQ.30 and 89% and 86% for the CES-D, respectively.!® Chronic/recurring GIO, depressive symptoms were de- fined in 2 ways: during the early phase of follow-up using data from 1985, 1989, and 1991, and nthe late phase using data from 1997, 2001, and 2008. Dementia ‘We used comprehensive tracing of electronic health records for dementia ascertainment using 3 databases: the national Hospital Episode Statistics database, the Mental Health Ser- vices Data Set, and the mortality register. The UK National Health Service uses in-house codes mapped onto Interna: tonal Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes for dementia. The National JAMA Psychiatry Jy2017 lume 74, Number? (© 2017 American Modical Association. Al rights resorved snetwork.com/ on 08/19/2021 nm Research rial investenion Health Service provides most of the health care; the Hospital [Episode Statistics database and Mental Health Services Data Set ate national databases with information on both inpa- tient and outpatient care, with the latter also including data foncarein the community. Record linkage until March 31,2015, Identified 322 cases of dementia: 172 eases were first re- corded in the hospitalization register, 42in the mental health register, and Bin the mortality register. ‘The validity of dementia cases in our study is supported bby modeling changesin the global cognitive score, composed oftests of memory reasoning, and phonemicand semantic u- ency administered tothe participants in 1997, 2003, 2007, and 2012." These results show accelerated decline in global cog- nitive score in the 8 o10 years before dementia diagnosis, as hasbeen shown in studies that use agold-standard dementia ascertainment procedure (eFigure 1 in the Supplement). Covariates (1985, 1991, 1897, and 2003) Sociodemographic factors included age, sex, race/ethnicity (white and nonwhite), marital status (martied/eohabiting vs other), education (no formal education, lower secondary school, higher secondary school, university, or higher de- agree), and occupational position, 23-level variable related to salary, social status, and level of responsibility at work.!? Health behaviorsincluded smoking (current, former, and never smoker), alcohol consumption (categorized as no/ ‘occasional, moderate 1-21 alcohol units per week formen and 14 alcohol units per week for women, and heavy [221 units pet week for men and 14 units per week for women), phys calactivity (hours per week of moderate or vigorous physical activity), and frequency of fruit and vegetable consumption (ess than once daily, once daily, or more than once daily) Health status included diabetes (fasting glucose level 2126.1 mgial. [to convert to millimoles per liter, multiply by 0.0555], 22-hourpostload glucose level >200 mia. reported physician-diagnosed diabetes, or use of diabetes medication); clinically assessed cardiovascular disease including coronary hear disease (International Statistical Classification of Diseases anc Related Health Problems, Tenth Revision codes:120-125)and stroke (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes: 160-164); cardiovascular disease medication, and antidepressant use. Statistical Analysis Associations between GHQ-30 casenessand participant char- acteristicsin 1985and 2003 were examined usingthe testand test. Two sets of analyses were performed, described here. As there were no sex differences in effect estimates (ll P for interaction between 13 and 98), men and women were com- bined in the analyses. Depressive Symptoms and incidence of Dementia ‘Theassociation of GHQ-30 casenessandiincidence of dementia was modeled using Cox regression; participants were censored atdate ofrecord of dementia, death toaccountforcompetingrisk ‘of mortality, or March 31, 2015, whichever came fist. These analyses were first undertaken using GHQ.40 (and covariates) rawn from 1985 and repeated using data from 1981, 1997, and JAMA Psychiatry y2017 Volume 74, Number TrajectonesofDepressve Symptons Before Dagross of Deets 2008, with mean follow-up of 26.6, 217, 16:3, and ILL years, spectively Wealso examined the association of CES-Decaseness| n2003andincidence of dementia. Allanalyses werefirstadjusted for sociodemographic measures (model D, then also for health behaviors (mode! 2), and finally for health covariates (model) Wethen examined the association of chronic/tecurring de- pressive symptoms (never, once, or 22 times) over the early study eriod (1985, 1989, and 1991) and ate study period (1997, 2001, and 200%) with incidence of dementia; covariatesin these analyses were drawn from 1991 and 2003, respectively. Follow-up for dementia began in 1991 foreatly-phase and 2003, forlate-phase depressive symptoms. Retrospective Analysis of28-Year Depressive Symptoms Trajectory Trajectories of GH10-30 depressive scores (range, 0-30) over 28, years were modeled usinga backward timescale such that year (0 (index date) was year of dementia for dementia cases, year of death for those who died during the follow-up, and March 31, 2015 (end of follow-up), forall others, The GHQ-30 score ineach of the28 years (year Oto year -28) was modeled using ‘mixed-effects models with the intercept and lopeasrandom effects." Dementia (coded as 1 or 0) and its interaction with slope terms (time, ime-squared, and time-cubed toallow for nonlinear change) were added tothe model to test for differ- encesin GH0-30 trajectoriesbetween those with dementiaand allothers. This modeling strategy implies that year 0 (the in- dex date) was the intercept in the analysis and the beta asso- ted with the dementia term yielded the dfferencein GHO-30 scorebetween those with and without dementiadiagnosis. We examined whether the terms dementia by time, dementia by time: squared, and dementiaby time-cubed improved fitof the ‘model using the Wald tes. Analyses were adjusted for age at year 0, sex, race/ethnicity, education, year of birth (-year categories), time-dependent occupational position, and ‘marital status. These analyses on GHO-30 trajectories were repeated using the CES-D score (range, 0-60) within a 12-year time window prior to dementia diagnosis. Analyses were undertaken using STATA version 14 (StataCorp) for analysis, A 2-sided P < .05 was considered statistically significant. Results OF the 10208 participants recruited to the study, data on (GHO-30 were available on 10189 participants n1985and 6728 participants in 2003; the study design flowchattis in eFigure 2 in the Supplement. Of the 3461 participants lost to follow-up over this period, 15.3% had died and 0.49had.ade~ ‘mentia diagnosis before 2003, Those without dataat the 2003, assessment were more likely tobe older (44.9 vs 44.7 yearsin 1985; P =.04), tobe women 41.1% 29.4%6;P <.0O1), and not hhave a university degree (79.6% vs 70.9%; P < 00D. Cases of dementia accrued mainly between 1996 and 2015, with 73% of cases recorded in the last 5 years of follow-up. Increasing age (hazard ratio [HRI for year greater age at study baseline, 1.21; 9596 Cl, 119-1.24), female sex (HR, 1.58; 95% Cl, 1.27- 1.96), and education less than secondary school diploma (HR, Jarapechntycon (© 2017 American Modical Association. Al rights resorved snetwork.com/ on 08/19/2021 ‘Tetris Depresve Symptoms Before Dingess of Dementia ‘rigalnvesigaion Resear “Table Caracas of the Study Population i a Function of GHO 30 Casenessin 1985 and 2003 (cHO-30 sees No(=7465),__Yesta= 2748), Ro@=s355), vem), oractrie 3 No.9 Pave We. Ne. value Fee 2344 GIA) 1017 G7)

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