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Cognition
Research paper
Depressive symptoms predict cognitive decline and dementia in older people independently of cerebral white matter changes: the LADIS study
  1. Ana Verdelho1,
  2. Sofia Madureira1,
  3. Carla Moleiro2,
  4. José M Ferro1,
  5. John T O'Brien3,
  6. Anna Poggesi4,
  7. Leonardo Pantoni4,
  8. Franz Fazekas5,
  9. Philip Scheltens6,
  10. Gunhild Waldemar7,
  11. Anders Wallin8,
  12. Timo Erkinjuntti9,
  13. Domenico Inzitari4,
  14. on behalf of the LADIS Study
  1. 1Department of Neurociences, University of Lisbon, Santa Maria Hospital, Lisbon, Portugal
  2. 2Psychology Department, Lisbon University Institute—ISCTE-IUL, Cis IUL, Lisbon, Portugal
  3. 3Institute for Ageing and Health, Newcastle University, UK
  4. 4NEUROFARBA Department, Neuroscience Section, University of Florence, Florence, Italy
  5. 5Department of Neurology and MRI Institute, Karl Franzens University Graz, Graz, Austria
  6. 6Department of Neurology, VU Medical Centre, Amsterdam, The Netherlands
  7. 7Memory Disorders Research Unit, Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark
  8. 8Institute of Clinical Neuroscience, Göteborg University, Göteborg, Sweden
  9. 9Memory Research Unit, Department of Clinical Neurosciences, Helsinki University, Helsinki, Finland
  1. Correspondence to Dr A Verdelho, Neurociences Department, Lisbon University, Santa Maria Hospital, 1649-035 Lisbon, Portugal; averdelho{at}fm.ul.pt

Abstract

Objective Depressive symptoms (DS) have been associated with increased risk of cognitive decline. Our aim was to evaluate the longitudinal influence of DS on cognition in independent older people, accounting for the severity of white matter changes (WMC).

Methods The LADIS (Leukoaraiosis And DISability in the elderly) prospective study evaluated the impact of WMC on the transition of independent older subjects into disability. Subjects were evaluated annually over a 3 year period with a comprehensive clinical and neuropsychological evaluation. Previous episodes of depression and current DS were assessed during each interview. Severity of DS was assessed using the self-rated 15 item Geriatric Depression Scale. A neuropsychological battery and clinical criteria for cognitive impairments were applied in all clinical visits, and cognitive compound measures were made based on neuropsychological results. MRI was performed at baseline and at year 3.

Results 639 subjects were included (74.1±5 years old, 55% women, 9.6±3.8 years of schooling). Dementia was diagnosed in 90 patients and cognitive impairment not dementia in 147 patients at the last clinical evaluation. DS were an independent predictor of cognitive impairment (dementia and not dementia) during follow-up, independent of the effect of the severity of WMC, medial temporal lobe atrophy, age, education or global cognitive function at baseline.

Conclusions DS are associated with an increase risk of cognitive decline, independent of the effect of WMC, probably due to an additive or synergistic effect. In this context, DS probably represent a subtle ongoing organic dysfunction

  • Cognition
  • Dementia
  • Depression
  • Cerebrovascular Disease

https://doi.org/10.1136/jnnp-2012-304191

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    Introduction

    Depressive symptoms have been associated with memory complaints1 and worse cognitive performance in non-demented older subjects,2 ,3 namely in the performance of executive functions,2 ,4 attention and processing speed.4 ,5 Moreover, cognitive impairment persists even after remission of late life depression, and older individuals who were previously cognitively intact before depression are often cognitively impaired in the remitted state of depression.6 However, conflicting data exist concerning depressive symptoms and risk of cognitive decline and dementia.3 ,7–,10 A meta-analysis concluded that history of depression was a risk factor for Alzheimer disease (AD) rather than a prodromal phase11 but a recent community cohort study could not find evidence to support this hypothesis.12 Some studies have found an increasing risk for AD10 ,13 whereas others found that the risk was associated with vascular dementia (VD) but not with AD.14

    Few studies have investigated neuropsychological performance in subjects with depressive symptoms taking into account cerebral white matter changes (WMC) and vascular risk factors. Two recent prospective studies failed to find vascular disease as a mediator of cognitive impairment and AD in depressive patients although confirmed depressive symptoms as a risk factor for AD or mild cognitive impairment (MCI).15 ,16 Others suggested that late onset depressed patients performed worse on neuropsychological testing and had more severe WMC.17–,20 An interesting cross sectional study showed associations between regional WMC and cognition in depressed subjects compared with non-depressed controls.21 Recently, WMC were found to be associated with increasing depressing symptoms,22 ,23 particularly deep WMC.24 Moreover, in recent published data from the LADIS (Leukoaraiosis And DISability) study, progression of WMC was significantly associated with incident depression over a 3 year follow-up period, implicating WMC in the causal pathogenesis of late life depression,25 Based on these results our aim was to (1) ascertain the influence of depressive symptoms on cognitive performance in a large sample of older subjects with WMC; (2) determine if the influence of depressive symptoms in cognition was lost when considering the effect of WMC severity; and (3) analyse this relationship over time.

    Methods

    The LADIS study is a prospective multinational European project involving 11 European centres (see online supplementary appendix 1 for a complete list of centres and staff) that explored the independent impact of WMC on the transition to functional disability in older people.26 Selection of participants had several sources: a medical appointment due to non-disabling unspecific complaints that included minor neurological, cognitive, mood or motor complaints or other neurological events; incidental WMC findings in brain imaging; controls in other studies; and volunteers willing to participate. The rationale, methodology and baseline assessment are described in full elsewhere.27 ,28 In short, inclusion criteria for the study were: (i) 65–84 years of age; (ii) presence of changes in WMC on MRI of any degree, according to the Fazekas scale29; (iii) no disability, as determined by the Instrumental Activities of Daily Living Scale.30 All subjects were assessed for demographic, medical and neurological, functional and quality of life status. Data were collected by trained medical personnel using a structured and comprehensive data questionnaire together with review of available records.27 All centre investigators were trained and provided with a specifically developed handbook with guidelines for applying criteria and tools.27 Depressive symptoms were assessed using the self-rated 15 item Geriatric Depression Scale (GDS),31 as it was specifically developed for older populations, was easy to use, was more focused on cognitive aspects and was less contaminated by somatic complaints associated with depressive symptoms. We recorded history of previous depression, defined as a past medical history of a depressive episode requiring treatment (ie, prescription of antidepressant medication, psychotherapy, electroconvulsive therapy) or hospital admission. MRI was performed at baseline and repeated at the 3 year follow-up. The degree of WMC severity was rated on axial FLAIR sequences by central readers blind to the clinical data using the three severity classes of a revised version of the Fazekas visual scale.29 Medial temporal lobe atrophy (MTA) was assessed on coronal T1 weighted sequences using the widely used and well validated rating scale of MTA.32

    The study protocol was approved by each centre's ethics committee. Participants gave signed informed consent before inclusion.

    Neuropsychological assessment and cognitive criteria

    Neuropsychological evaluation was performed at all clinical visits. References for neuropsychological tests and cognitive criteria are given in the online supplementary appendix 2. The neuropsychological battery included the Mini-Mental State Examination (MMSE) as a global measure of cognitive function; the VADAS-Cog (the Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) plus delayed recall, symbol digit, digit span, mazes, digit cancellation and verbal fluency) as a comprehensive instrument to assess orientation, language, ideational and constructional praxis, immediate memory and delayed recall, and the Stroop and Trail Making (TM) tests as measures of executive function. Tests were grouped by cognitive domains to simplify the clinical interpretation of neuropsychological results. A compound measure for three main domains was calculated using standard scores of individual tests: (1) memory=z scores (immediate word recall+delayed recall+word recognition+digit span)/4; (2) executive functions=z scores of ((Stroop3-2)+(TMB-TMA)+symbol digit+verbal fluency)/4; and (3) speed and motor control=z scores (TMA+mazes+digit cancellation)/3. Higher scores in VADAS and ADAS-Cog mean worse cognitive performance. Higher values in compound measures mean better performance. Detailed explanation about the LADIS neuropsychological battery has been previously described.26

    In addition, in the follow-up clinical visits, patient cognitive status was classified by the clinician into the following groups: (1) demented; (2) cognitive impairment not demented; and (3) no cognitive impairment. For this purpose, we used the following criteria and definitions. We considered two types of cognitive decline not dementia: (1) amnestic MCI, according to Petersen et al (defined as memory complaint, preferably corroborated by an informant; impaired memory function for age and education, preserved general cognitive function, intact activities of daily living and no dementia) and vascular cognitive impairment, no dementia (defined as evidence of cognitive impairment and clinical consensus to identify significantly related vascular features; exclusion of dementia when impairments were not sufficiently severe to interfere with social or occupational functioning or when impairments were more focal than the global requirement for a diagnosis of dementia). If dementia was present, we considered the following criteria for subtypes: probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) Work Group, probable VD according to the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria, subtype of subcortical VD according to Erkinjuntti et al, frontotemporal dementia according to McKhann et al and dementia with Lewy bodies. AD with a cerebrovascular disease diagnosis was made when the investigator judgement considered that the clinical picture presented both aspects of AD and VD, and in accordance with NINDS-AIREN criteria. Progression of cognitive impairment (or decline) during the study was defined as a change in the ‘clinical cognitive diagnosis’ over follow-up—that is, decline was determined by transition from ‘no cognitive impairment’ to ‘cognitive impairment no dementia’ or to ‘dementia’.

    Statistical analysis

    Baseline assessment

    The influence of the severity of depressive symptoms and of previous depression on neuropsychological performance at baseline was analysed by multiple linear regression analyses using the different neuropsychological scores as the dependent variable. We considered, for the present study, the following dependent variables: global measures of cognition (VADAS-Cog and MMSE) and main cognitive domains, as described (memory, executive functions and speed/motor control). We postulated that if depressive symptoms were significant predictors of cognitive measures, independent of WMC, then depressive symptoms (measured by means of the GDS) should add significant variance in the model when taking into account WMC severity score. Scores for neuropsychological tests, compound measures and GDS were considered as continuous variables. Linear regression analyses were adjusted for age, gender, educational level, WMC severity, MTA and history of previous depression.

    Longitudinal assessment

    The influence of depressive symptom severity and of previous depression on cognitive status over time was assessed using the Cox proportional hazards model. As a dependent variable, we considered the results of last cognitive evaluation of each patient, as described in the methods section: any cognitive decline (dementia and cognitive impairment not dementia) versus no cognitive decline in the last observation. We considered previous depression and GDS score as independent variables. Following the methodology of O'Brien et al of the LADIS group,22 we divided the range of GDS scores into quintiles because, as would be expected in a community dwelling population, the depression rating scores were heavily skewed towards low values. We adjusted analyses for age, gender, educational level, WMC severity and MTA. Age and educational level were considered continuous variables. Presence of previous depression, GDS quintiles, gender, MTA and WMC severity were considered categorical variables. We repeated the Cox proportional hazards model controlling also for the cognitive global measures at baseline (MMSE). Data were analysed using SPSS V.16.0 software.

    Results

    A total of 639 subjects were included (74.1±5 years old, 55% women, 9.6±3.8 years of schooling). The characteristics of the study sample at baseline are presented in table 1.

    View this table:
    Table 1

    Sample characteristics at baseline (n=639)

    At the end of follow-up it was possible to ascertain vital status or Instrumental Activities of Daily Living in 633 patients (99.1% of the initial sample). In the whole sample, 51 patients missed complete cognitive evaluation in any follow-up clinical visit. Considering the cognitive diagnosis ascertained in the last clinical visit (excluding the 51 patients with no cognitive diagnosis attributed), dementia was diagnosed in 90 patients during the study (VD n=54; AD and AD with vascular component n=34; frontotemporal dementia n=2), and 147 patients had cognitive impairment not dementia (vascular cognitive impairment, no dementia n=86; MCI n=61).

    GDS items more frequently reported by the included subjects were: item 13—“Do you feel full of energy?” (262 subjects) and item 9 —“Do you prefer to stay at home, rather than going out and doing new things” (260 subjects); followed by item 10 —“Do you feel that you have more problems with your memory than most?” (218 subjects) and item 2—“Have you dropped many of your activities and interests?” (208 subjects).

    Relations between cognitive evaluation and GDS score at baseline

    Using multiple linear regression analysis, we found that depressive symptoms (measured by the GDS score) at baseline were associated with poorer performance in global measures of cognition (MMSE and VADAS-COG), cognitive compound measures of executive functions, speed and motor control, and memory, independent of other potential confounders (table 2). Previous history of depression was not significantly associated with performance in cognitive measures at baseline. WMC severity was independently associated with worse performance in the MMSE and compound measures of executive functions and speed and motor control, but not in the compound measure of memory (table 2).

    View this table:
    Table 2

    Associations between cognitive evaluation (global and compound measures) and Geriatric Depression Scale score at baseline

    Longitudinal impact of depressive symptoms and previous depression in cognition

    Using Cox proportional hazards model we found that GDS score at baseline was an independent predictor of cognitive impairment (dementia and cognitive impairment not dementia) in the follow-up (table 3).

    View this table:
    Table 3

    Cox proportional hazards model, dependent variable: cognitive decline (combined dementia and cognitive impairment not dementia)

    This effect was independent of the effect of severity of WMC. Severe WMC remained a predictor of cognitive decline. Previous depression was not a predictor of cognitive impairment.

    Controlling for the global cognitive measure at baseline, the predictive effect of GDS score was unchanged (table 4).

    View this table:
    Table 4

    Cox proportional hazards model controlling for Mini-Mental State Examination at baseline

    We also controlled the analyses for physical activity and for diabetes (results not shown, available if requested), and the impact of depressive symptoms in cognitive outcome remained unchanged.

    Discussion

    Our study showed that, in older subjects with WMC living with full autonomy, depressive symptoms were associated with worse cognitive performance (in global cognitive measures, executive functions and speed) at baseline and were predictors of further cognitive decline over a 3 year follow-up period, independent of the severity of WMC. The same results were observed when controlling for different factors, such as global cognitive performance at baseline, physical activity or diabetes, reinforcing the impact of depressive symptoms on cognitive outcome.

    The strengths of the study include a large sample size of rigorously assessed older people, the prospective nature of the study and the possibility of carefully controlling for other variables implicated in cognition (age, education, medial temporal atrophy). Our study has some limitations, related to sample selection. We designed the study to investigate subjects with WMC, the sample was not community based and selection of subjects was heterogeneous. Although they represent an important part of the elderly population that come to seek medical attention, we must be cautious in the generalisation of the results.25 ,33 Another limitation was the absence of information on social and leisure activities although we included physical activity.

    One of the controversial aspects in the associations between depressive symptoms and cognitive performance in cross sectional analyses is that we can hypothesise that depressive symptoms interfere with cognitive task performance but has no further impact on cognition.1 ,2 ,4 ,5 Furthermore, the relationship between depressive symptoms and cognitive decline is complex. Depressive symptoms can appear as an initial manifestation of an incipient cognitive change or can be interpreted as a risk factor for cognitive decline, or otherwise be a concomitant disease and could be a result of awareness of cognitive difficulties, as suggested by previous authors.3 ,7 ,8 ,10 ,11 ,34 Some biological explanations have been proposed to understand the association between depressive symptoms and cognitive decline, including hyperactivity of the hypothalamic–pituitary–adrenal axis with enhanced adrenal responsiveness to adrenocorticotropic hormone and glucocorticoid negative feedback with subsequent hypercortisolaemia,35 and also glucose intolerance, reduced heart rate, platelet reactivity and the presence of inflammatory proteins secondary to depression.36 It has also been pointed out that patients with depression can adapt an unhealthy lifestyle as well as poor medication adherence.37

    In the Rotterdam study, history of depression (particularly of early onset), but not presence of depressive symptoms, was associated with an increased risk of AD.9 In the Italian Study on Aging, depressive symptoms at baseline predicted change over time of global cognitive decline,38 similar to the 3C study.14 In these studies, WMC were not taken into account. Few reports approached the evolution of subjects with depressive symptoms taking into account WMC.39 An interesting cross sectional study showed associations between regional locations of WMC and cognitive function, compared with controls, but no further longitudinal evolution was reported.21 In the LADIS study, WMC severity at baseline predicted depressive symptoms at 2 and 3 years of follow-up40 and furthermore, progression of WMC was significantly associated with incident depression during the 3 year period of the study.25 In this study, depressive symptoms predicted cognitive impairment, independent of the effect of WMC. Our results are consistent with the hypothesis that depressive symptoms are an expression of vascular damage due to frontostriatal disconnection and not a true depression. Some detailed pathological studies have supported this view,41 but in a recent community based study conducted with neuropathological examination, late life depression was not associated with cerebrovascular or Alzheimer pathology.42

    In conclusion, we found that WMC and depressive symptoms independently predicted dementia in older subjects. GDS items more frequently reported by our sample represent more accurately cognitive difficulties rather than a mood disorder. It is possible that depressive symptoms and WMC have an additive or synergistic effect for the future development of dementia. These results may support the idea that depressive symptoms, as measured in our sample, do not represent a mood disorder, but rather an organic dysfunction. Thus our results shed important new light on the relation between depressive symptoms, vascular pathology and cognitive impairment. We believe that this subject deserves better clarification with prospective studies that should carefully control imagiological vascular biomarkers.

    Acknowledgments

    We thank Dr Ana Catarina Oliveira Santos for the technical advice in the statistical approach.

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      OpenUrlAbstract/FREE Full Text

    Supplementary materials

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    Footnotes

    • Contributors AV made substantial contributions to the conception and design, acquisition of the data, analysis and interpretation of the data, drafting the article for intellectual content, revising the article and final approval of the version to be submitted. SM made substantial contributions to the conception and design, acquisition of the data, analysis and interpretation of the data, draft and revision of the paper for intellectual content and final approval of the version to be submitted. CM made substantial contributions to analysis and interpretation of the data, revising the paper critically for important intellectual content and final approval of the version to be submitted. JMF made substantial contributions to conception and design and interpretation of the data, revising the article critically for important intellectual content and final approval of the version to be submitted. JTO made substantial contributions to conception and design, interpretation of the data, revising the article critically for important intellectual content and final approval of the version to be published. AP made substantial contributions to conception and design, acquisition of the data, analysis and interpretation of the data, revising the paper critically for important intellectual content and final approval of the version to be published. LP made substantial contributions to conception and design, acquisition of the data, analysis and interpretation of the data, revising the article critically for important intellectual content and final approval of the version to be published. FF made substantial contributions to conception and design, acquisition of the data, revising the article critically for important intellectual content and final approval of the version to be published. PS made substantial contributions to conception and design, acquisition of the data, revising the article critically for important intellectual content and final approval of the version to be published. GW made substantial contributions to conception and design, acquisition of the data, revising the paper critically for important intellectual content and final approval of the version to be published. AW made substantial contributions to conception and design, revising the paper critically for important intellectual content and final approval of the version to be published. TE made substantial contributions to conception and design, revising the paper critically for important intellectual content and final approval of the version to be published. DI made substantial contributions to conception and design, revising the paper critically for important intellectual content and final approval of the version to be published.

    • Funding The LADIS study was supported by the European Union within the Vth European Framework Program ‘Quality of life and management of living resources’ (1998–2002), contract No QLRT-2000-00446.

    • Competing interests None.

    • Ethics approval The study protocol was approved by each centre's ethics committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.