Strengths and Weaknesses of the Vascular Apathy Hypothesis: A Narrative Review.

The vascular apathy hypothesis states that cerebral small vessel disease (CSVD) can cause apathy, even when no other symptoms of CSVD are present. In order to examine this hypothesis, the objectives of this narrative review are to evaluate the evidence for a pathophysiological mechanism linking CSVD to apathy and to examine whether CSVD can be a sole cause of apathy. The nature of the CSVD-apathy relationship was evaluated using the Bradford Hill criteria as a method for research on the distinction between association and causation. Pathological, neuroimaging, and behavioral studies show that CSVD can cause lesions in the reward network, which causes an apathy syndrome. Studies in healthy older individuals, stroke patients and cognitively impaired persons consistently show an association between CSVD markers and apathy, although studies in older persons suffering from depression are inconclusive. A biological gradient is confirmed, as well as a temporal relationship, although the evidence for the latter is still weak. The specificity of this causal relationship is low given there often are other contributing factors in CSVD patients with apathy, particularly depression and cognitive deterioration. Differentiating between vascular apathy and other apathy syndromes on the basis of clinical features is not yet possible, while in-depth knowledge about differences in the prognosis and efficacy of treatment options for apathy caused by CSVD and other apathy syndromes is lacking. Since we cannot differentiate between etiologically different apathy syndromes as yet, it is premature to use the term vascular apathy which would suggest a distinct clinical apathy syndrome.

Empirical support for the vascular apathy hypothesis: A structured review.

OBJECTIVES: A systematic review of the relationship between subclinical small vessel disease (SSVD) in the general population and apathy to examine the hypothesis that apathy has a vascular basis. METHODS: We searched for studies on associations between apathy and SSVD, operationalized as white matter hyperintensities (WMH) or white matter diffusivity changes, lacunar infarcts, cerebral microbleeds, decreasing cortical thickness, and perivascular spaces, while also peripheral proxies for SSVD were considered, operationalized as ankle brachial pressure index (ABI), intima media thickness, arterial stiffness, cardio-femoral pulse wave velocity, hypertension, or cardiovascular disease. Only eligible retrospective and prospective observational studies conducted in the general population were included. RESULTS: The 14 studies eligible for review examined the associations between apathy and hypertension (3), ABI (1), arterial stiffness (1), cardiovascular disease (2), WMH (3), white matter diffusivity (2), cerebral microbleeds (1), or cortical thickness (3). Arterial stiffness and white matter diffusivity were not related to apathy, while the associations with cortical thickness were contradictory. Cross-sectional studies in the general population did find evidence of apathy being associated with WMH, CM, cardiovascular disease, hypertension, and ABI, and cardiovascular disease was prospectively associated with apathy. The methodologies of the studies reviewed were too heterogeneous to perform meta-analyses. CONCLUSIONS: Although more prospective evidence is needed and vascular depression needs to be controlled for, cardiovascular disease, hypertension, and ABI as proxies for SSVD, and WMH and cerebral microbleeds as direct measures of SSVD have been found to be associated with apathy in the general population, supporting the hypothesis of vascular apathy.

Depression in context of low neuroticism is a risk factor for stroke: a 9-year cohort study.

OBJECTIVE: Depression predicts stroke; however, meta-analyses show significant heterogeneity. We hypothesize that the risk of depression on incident stroke is conditional upon the relative contribution of vascular disease and of neuroticism in the underlying pathways to depression in a specific patient. We examined whether depression increases stroke in persons with low neuroticism and without preexisting cardiac disease. METHODS: This was a population-based cohort study with 9-year follow-up (n = 2,050; ≥55 years, 52% female). The incidence of stroke was determined by self-report data as well as data from general practitioners and death certificates. Neuroticism was measured using the Dutch Personality Questionnaire and depression using the Center for Epidemiologic Studies-Depression scale. All data were analysed by Cox proportional hazards regression. RESULTS: A total of 117 incident cases of stroke occurred during follow-up. Among persons with a history of cardiac disease (n = 401), depression predicted incident stroke independent of neuroticism level with a hazard ratio (HR) of 1.05 (95% confidence interval [CI] 1.01-1.10) (p = 0.02). In persons without cardiac disease (n = 1,649), depression and neuroticism interacted significantly in predicting incident stroke (p = 0.028). Stratified analyses showed that depression predicted incident stroke in those with low neuroticism, HR 1.05 (95% CI 1.00-1.09) (p = 0.033), but not in those with high neuroticism, HR 1.01 (95% CI 0.96-1.05) (p = 0.82). CONCLUSIONS: In persons without preexistent cardiac disease, depression is only predictive for future stroke in absence of high neuroticism. This might be explained by the hypothesis that late-life depression in context of low neuroticism is a marker of subclinical vascular disease.

Atherosclerosis decreases the impact of neuroticism in late-life depression: hypothesis of vascular apathy.

OBJECTIVE: To examine the interplay between subclinical atherosclerotic disease and neuroticism in explaining variance in late-life depressive symptoms. METHODS: This study was part of the Nijmegen Biomedical Study, a population-based survey; 1,517 participants aged 50-70 years were included. Depressive symptoms were measured by the Beck Depression Inventory (BDI). Principal components analysis of the BDI items yielded two factors, representing a cognitive-affective symptom cluster and a somatic-affective symptom cluster. Atherosclerotic disease was measured by the intima media thickness (IMT) of the carotid arteries and neuroticism by the revised Eysenck Personality Questionnaire. RESULTS: Multiple linear regression analyses using different measures of depressive symptoms as the dependent variable showed that neuroticism was strongly and significantly associated with the sum score of the BDI and with the two depressive symptom clusters. IMT, however, was only significantly associated with the somatic-affective symptom cluster but not with the cognitive-affective symptom cluster. Interestingly, we found a significant negative interaction between neuroticism and IMT in explaining the severity of the cognitive-affective symptom cluster but not with respect to the somatic-affective symptom cluster. CONCLUSION: The negative interaction between neuroticism and atherosclerosis indicates that neuroticism is less strongly associated with cognitive-depressive symptoms in the presence of more severe atherosclerosis. This may be explained by apathy due to cerebrovascular disease and fits with a hypothesis of vascular apathy.

Cardiac disease, depressive symptoms, and incident stroke in an elderly population.

CONTEXT: Previous research suggests that depression is a risk factor for stroke. However, the reliability of much research is limited by the lack of documentation on the presence of preexistent cardiovascular disease and by the use of limited measures of depression or stroke. OBJECTIVES: To test the hypotheses that (1) clinically relevant depressive symptoms are an independent risk factor of incident stroke in cardiac and noncardiac patients and (2) more chronic and severe depressive symptoms are associated with incident stroke. DESIGN: A cohort of elderly Dutch people (aged > or = 55 years) was followed up for 9 years in the Longitudinal Aging Study Amsterdam (baseline measurements were taken in 1992 or 1993, and the study concluded in 2001 or 2002, respectively). SETTING: General community. PARTICIPANTS: Randomly selected population-based sample (N = 2965) without a history of stroke. MAIN OUTCOME MEASURES: The study end point was a first stroke (nonfatal or fatal). Depression was measured using the National Institute of Mental Health Diagnostic Interview Schedule and the Center for Epidemiological Studies-Depression Scale. Multivariate Cox proportional hazards regression analyses of stroke incidence were performed. The association of the chronicity and severity of depressive symptoms was studied in extended models with time-dependent variables. RESULTS: The sample's mean (SD) age was 70.5 (8.7) years, 52.1% were women, and the mean (SD) follow-up was 7.7 (3.1) years. Inclusion of an interaction between cardiac disease and clinically relevant depressive symptoms improved the model for stroke (P = .03). In participants with preexistent cardiac disease, but not in participants without cardiac disease, clinically relevant depressive symptoms at baseline (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.17-4.09) and the severity (range, 0-60; HR, 1.08; 95% CI, 1.02-1.13) and chronicity (HR, 3.51; 95% CI, 1.13-10.93) of symptoms during follow-up were associated with stroke. CONCLUSIONS: Preexistent cardiac disease moderates the association between depressive symptoms and incident stroke. In cardiac patients, baseline depressive symptoms and both the severity and chronicity of symptoms during follow-up are associated with incident stroke.