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Microvascular Contribution to Late-Onset Depression: Mechanisms, Current Evidence, Association With Other Brain Diseases, and Therapeutic Perspectives

Open AccessPublished:April 27, 2021DOI:https://doi.org/10.1016/j.biopsych.2021.04.012

      Abstract

      Depression is common in older individuals and is associated with high disability and mortality. A major problem is treatment resistance: >50% of older patients do not respond to current antidepressants. Therefore, new effective interventions for prevention and treatment of depression in older individuals need to be developed, which requires a better understanding of the mechanisms underlying depression. The pathophysiology of depression is multifactorial and complex. Microvascular dysfunction may be an early and targetable mechanism in the development of depression, notably depression that initiates in late life (late-onset depression). Late-onset depression commonly co-occurs with other diseases or syndromes that may share a microvascular origin, including apathy, cognitive impairment, dementia, and stroke. Together, these disabilities may all be part of one large phenotype resulting from global cerebral microvascular dysfunction. In this review, we discuss the pathophysiology of microvascular dysfunction–related late-onset depression, summarize recent epidemiological evidence on the association between cerebral microvascular dysfunction and depression, and indicate potential drivers of cerebral microvascular dysfunction. We also propose the hypothesis that depression may be a manifestation of a larger phenotype of cerebral microvascular dysfunction, highlight potential therapeutic targets and interventions, and give directions for future research.

      Keywords

      Depression is a large contributor to global disability in older individuals. Major depression occurs in 2% of adults aged 65 years or older, and its prevalence rises with increasing age. In addition, 10% to 15% of older adults have clinically significant depressive symptoms, even in the absence of major depression (
      • Kok R.M.
      • Reynolds 3rd, C.F.
      Management of depression in older adults: A review.
      ). Major depression and depressive symptoms in older adults are associated with frailty (
      • Lyness J.M.
      • Heo M.
      • Datto C.J.
      • Ten Have T.R.
      • Katz I.R.
      • Drayer R.
      • et al.
      Outcomes of minor and subsyndromal depression among elderly patients in primary care settings.
      ), lower quality of life (
      • Chachamovich E.
      • Fleck M.
      • Laidlaw K.
      • Power M.
      Impact of major depression and subsyndromal symptoms on quality of life and attitudes toward aging in an international sample of older adults.
      ), and 1.5- to 2-fold higher mortality risk (
      • Barefoot J.C.
      • Schroll M.
      Symptoms of depression, acute myocardial infarction, and total mortality in a community sample.
      ,
      • Penninx B.W.
      • Geerlings S.W.
      • Deeg D.J.
      • van Eijk J.T.
      • van Tilburg W.
      • Beekman A.T.
      Minor and major depression and the risk of death in older persons.
      ). However, current antidepressant medications targeting neurotransmitters are less effective (
      • Tedeschini E.
      • Levkovitz Y.
      • Iovieno N.
      • Ameral V.E.
      • Nelson J.C.
      • Papakostas G.I.
      Efficacy of antidepressants for late-life depression: A meta-analysis and meta-regression of placebo-controlled randomized trials.
      ,
      • Calati R.
      • Salvina Signorelli M.
      • Balestri M.
      • Marsano A.
      • De Ronchi D.
      • Aguglia E.
      • Serretti A.
      Antidepressants in elderly: Metaregression of double-blind, randomized clinical trials.
      ) and have more side effects (
      • Coupland C.
      • Dhiman P.
      • Morriss R.
      • Arthur A.
      • Barton G.
      • Hippisley-Cox J.
      Antidepressant use and risk of adverse outcomes in older people: Population based cohort study.
      ) in older patients than in younger patients. More than 50% of older patients do not respond to such treatment (
      • Thomas A.
      • O’Brien J.T.
      Management of late-life depression: A major leap forward.
      ). Given the aging society, better understanding of the underlying mechanisms of depression in older individuals is required so that more effective prevention and treatment strategies can be developed.
      The pathophysiology of late-life depression is multifactorial and complex. Patients with late-life depression are a heterogeneous group, including individuals with late-onset depression, in whom the initial depressive episode occurs after age 60 years, and individuals with early-onset depression who already had a first depressive episode earlier in life (
      • Taylor W.D.
      • Aizenstein H.J.
      • Alexopoulos G.S.
      The vascular depression hypothesis: Mechanisms linking vascular disease with depression.
      ). Several years ago, it was postulated that cerebrovascular damage may contribute to depression via disruption of brain regions involved in mood regulation (
      • Alexopoulos G.S.
      • Meyers B.S.
      • Young R.C.
      • Campbell S.
      • Silbersweig D.
      • Charlson M.
      ‘Vascular depression’ hypothesis.
      ), notably, damage to subcortical regions (
      • Taylor W.D.
      • Steffens D.C.
      • Krishnan K.R.
      Psychiatric disease in the twenty-first century: The case for subcortical ischemic depression.
      ,
      • Krishnan K.R.
      • Taylor W.D.
      • McQuoid D.R.
      • MacFall J.R.
      • Payne M.E.
      • Provenzale J.M.
      • Steffens D.C.
      Clinical characteristics of magnetic resonance imaging-defined subcortical ischemic depression.
      ). This mechanism may be particularly relevant in older individuals without a history of depression (i.e., late-onset depression). Subsequent studies have identified evidence for this vascular depression hypothesis (
      • Taylor W.D.
      • Aizenstein H.J.
      • Alexopoulos G.S.
      The vascular depression hypothesis: Mechanisms linking vascular disease with depression.
      ,
      • Aizenstein H.J.
      • Baskys A.
      • Boldrini M.
      • Butters M.A.
      • Diniz B.S.
      • Jaiswal M.K.
      • et al.
      Vascular depression consensus report - A critical update.
      ,
      • Alexopoulos G.S.
      Mechanisms and treatment of late-life depression.
      ) and suggest that vascular depression may be a specific subtype of depression (Table 1). However, these studies mostly focused on late stages of cerebrovascular disease when irreversible brain damage was already evident. For effective interventions, it is crucial to identify mechanisms that can be targeted in an early stage of the disease before irreversible damage occurs.
      Table 1Selected Key Terms and Definitions
      TermsDefinition and Comments
      Depression HeterogeneityDepression is a highly heterogeneous syndrome driven by varying genetic and neurophysiological mechanisms, which give rise to varying symptom profiles, clinical trajectories, and treatment outcomes. This heterogeneity may be more apparent in late-life depression, because aging-related changes across multiple organ systems may contribute to depression (
      • Taylor W.D.
      • Aizenstein H.J.
      • Alexopoulos G.S.
      The vascular depression hypothesis: Mechanisms linking vascular disease with depression.
      ).
      Vascular DepressionA subtype of depression characterized by a distinct clinical presentation and an association with cerebrovascular damage. A recent consensus report (
      • Aizenstein H.J.
      • Baskys A.
      • Boldrini M.
      • Butters M.A.
      • Diniz B.S.
      • Jaiswal M.K.
      • et al.
      Vascular depression consensus report - A critical update.
      ) suggested the following criteria for vascular depression: 1) evidence of vascular pathology in elderly subjects with or without cognitive impairment, 2) absence of previous depressive episodes preceding obvious cerebrovascular disease, 3) presence of cerebrovascular risk factors, 4) coincidence of depression with cerebrovascular risk factors, 5) clinical symptoms characteristic of vascular depression (executive dysfunction, decrease in processing speed, and lethargy), and 6) neuroimaging data confirming cerebrovascular disease. However, these diagnostic criteria for vascular depression are, until now, not widely accepted, and vascular depression has not been included in formal psychiatric manuals.
      Cerebral Microvascular Function and DysfunctionCore functions of the cerebral microcirculation, defined as cerebral vessels with a diameter <150 μm (arterioles, capillaries, and venules), are to 1) optimize the delivery of nutrients and removal of waste products in response to variations in neuronal activity, 2) maintain the cerebral interstitial milieu for proper cell function, and 3) decrease and stabilize pulsatile hydrostatic pressure at the level of capillaries (
      • Wardlaw J.M.
      • Smith C.
      • Dichgans M.
      Small vessel disease: Mechanisms and clinical implications.
      ,
      • van Sloten T.T.
      • Sedaghat S.
      • Carnethon M.R.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral microvascular complications of type 2 diabetes: Stroke, cognitive dysfunction, and depression.
      ). Cerebral microvascular dysfunction is defined as an impairment in any of these functions.
      Blood-Brain BarrierA tightly linked monolayer of endothelial cells, together with a basement membrane, astrocyte end feet, and mural cells (pericytes in capillaries and vascular smooth muscle cells in arterioles). The blood-brain barrier separates the circulating blood and brain compartments and strictly regulates blood-to-brain and brain-to-blood transport of solutes to maintain the highly controlled internal milieu of the central nervous system (
      • Wardlaw J.M.
      • Smith C.
      • Dichgans M.
      Small vessel disease: Mechanisms and clinical implications.
      ,
      • Sweeney M.D.
      • Sagare A.P.
      • Zlokovic B.V.
      Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders.
      ).
      Neurovascular CouplingMechanism by which the brain can rapidly increase local blood flow to activated neurons (
      • Kisler K.
      • Nelson A.R.
      • Montagne A.
      • Zlokovic B.V.
      Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease.
      ). Upon an increase in neuronal activity, astrocytes signal to endothelial cells the paracrine release of vasoactive agents. These signals engage smooth muscle cells and, possibly, pericytes to induce vasodilatation, reduce cerebrovascular resistance, and increase local cerebral blood flow (
      • Willie C.K.
      • Tzeng Y.C.
      • Fisher J.A.
      • Ainslie P.N.
      Integrative regulation of human brain blood flow.
      ).
      Cerebral AutoregulationAbility of the cerebrovasculature to maintain a constant level of global brain perfusion despite varying arterial blood pressure (
      • Willie C.K.
      • Tzeng Y.C.
      • Fisher J.A.
      • Ainslie P.N.
      Integrative regulation of human brain blood flow.
      ). This ensures a relatively constant level of blood flow to meet the high metabolic demand of the brain (
      • Raichle M.E.
      • Gusnard D.A.
      Appraising the brain’s energy budget.
      ). Arterioles together with larger cerebral arteries regulate this response by varying cerebrovascular resistance mediated by myogenic responses (
      • Willie C.K.
      • Tzeng Y.C.
      • Fisher J.A.
      • Ainslie P.N.
      Integrative regulation of human brain blood flow.
      ).
      Albumin QuotientRatio of cerebrospinal fluid albumin to serum albumin level. Albumin originate solely from the systemic circulation and cannot cross an intact blood-brain barrier. An increase in the albumin quotient can, thus, be used as an indirect measure of blood-brain permeability.
      Cerebrovascular ReactivityChange in flow in response to increased neuronal activity (i.e., neurovascular coupling) or a metabolic or vasodilatory stimulus, e.g., increase in partial pressure of carbon dioxide (
      • Thrippleton M.J.
      • Shi Y.
      • Blair G.
      • Hamilton I.
      • Waiter G.
      • Schwarzbauer C.
      • et al.
      Cerebrovascular reactivity measurement in cerebral small vessel disease: Rationale and reproducibility of a protocol for MRI acquisition and image processing.
      ). This response reflects the ability of the cerebrovasculature, notably, arterioles and capillaries, to dilate in response to increased neuronal metabolic demand and is endothelium-dependent (
      • Willie C.K.
      • Tzeng Y.C.
      • Fisher J.A.
      • Ainslie P.N.
      Integrative regulation of human brain blood flow.
      ,
      • Ainslie P.N.
      • Duffin J.
      Integration of cerebrovascular CO2 reactivity and chemoreflex control of breathing: Mechanisms of regulation, measurement, and interpretation.
      ).
      We propose that microvascular dysfunction is an early and targetable mechanism in the development of late-onset depression. Late-life depression commonly co-occurs with other syndromes or diseases that may share a microvascular origin, including apathy, cognitive impairment, dementia, and stroke. Together, these disabilities may all be part of one large phenotype resulting from global cerebral microvascular dysfunction.
      In this review, we discuss the functions of the cerebral microvasculature and how microvascular dysfunction may contribute to the development of late-onset depression. Cerebral microvascular dysfunction is the overlying construct that includes (or can be defined by) blood-brain barrier leakage, impaired cerebral autoregulation, impaired neurovascular coupling, and disturbed capillary flow patterns (
      • Wardlaw J.M.
      • Smith C.
      • Dichgans M.
      Small vessel disease: Mechanisms and clinical implications.
      ,
      • van Sloten T.T.
      • Sedaghat S.
      • Carnethon M.R.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral microvascular complications of type 2 diabetes: Stroke, cognitive dysfunction, and depression.
      ) (Table 1). We review emerging evidence that cerebral microvascular dysfunction and damage are present in older individuals with depression and are associated with apathy, cognitive dysfunction, and stroke in these individuals. We will also indicate which factors may contribute to cerebral microvascular dysfunction in depression, highlight potential interventions, and give directions for future research.
      In discussing these issues, we rely to an important extent on data obtained in humans, because currently, no experimental model exists that approximates the complex underlying mechanisms and heterogeneous manifestations of late-onset depression in patients. However, experimental studies are crucial to understand the individual causative pathways by which impairment of the different functions of the microvasculature can contribute to depressive symptoms. For example, recent basic studies have provided important insights into the role of stress susceptibility and blood-brain barrier leakage in the development of depressive symptoms. These studies suggest that maintenance of blood-brain barrier integrity could represent an approach to develop therapeutic strategies to treat depression. This has been discussed in recent reviews (
      • Dudek K.A.
      • Dion-Albert L.
      • Kaufmann F.N.
      • Tuck E.
      • Lebel M.
      • Menard C.
      Neurobiology of resilience in depression: Immune and vascular insights from human and animal studies.
      ,
      • Cathomas F.
      • Murrough J.W.
      • Nestler E.J.
      • Han M.H.
      • Russo S.J.
      Neurobiology of resilience: Interface between mind and body.
      ,
      • Tsyglakova M.
      • McDaniel D.
      • Hodes G.E.
      Immune mechanisms of stress susceptibility and resilience: Lessons from animal models.
      ).

      Functions of the Cerebral Microvasculature

      Optimal function of the brain depends on a healthy microvasculature (
      • Sweeney M.D.
      • Zhao Z.
      • Montagne A.
      • Nelson A.R.
      • Zlokovic B.V.
      Blood-brain barrier: From physiology to disease and back.
      ,
      • Willie C.K.
      • Tzeng Y.C.
      • Fisher J.A.
      • Ainslie P.N.
      Integrative regulation of human brain blood flow.
      ). The cerebral microcirculation represents the site of resistance to flow and the surface of exchanges. It is the major component of the blood-brain barrier and has a crucial role in the regulation of cerebral perfusion via control of neurovascular coupling and cerebral autoregulation (Table 1) (
      • Wardlaw J.M.
      • Smith C.
      • Dichgans M.
      Small vessel disease: Mechanisms and clinical implications.
      ,
      • van Sloten T.T.
      • Sedaghat S.
      • Carnethon M.R.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral microvascular complications of type 2 diabetes: Stroke, cognitive dysfunction, and depression.
      ,
      • Stehouwer C.D.A.
      Microvascular dysfunction and hyperglycemia: A vicious cycle with widespread consequences.
      ).

      Contribution of Microvascular Dysfunction to Depression

      The mechanistic pathways by which microvascular dysfunction may contribute to depression are shown in Figures 1 and 2. Microvascular dysfunction includes increased blood-brain permeability and impaired blood perfusion regulation, with disturbed neurovascular coupling and cerebral autoregulation (
      • van Sloten T.T.
      • Sedaghat S.
      • Carnethon M.R.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral microvascular complications of type 2 diabetes: Stroke, cognitive dysfunction, and depression.
      ). These impairments can each lead to focal brain injury, which may damage neuronal circuits involved in mood regulation and contribute to clinical depressive symptoms and negatively influence the effect of antidepressants (
      • Taylor W.D.
      • Aizenstein H.J.
      • Alexopoulos G.S.
      The vascular depression hypothesis: Mechanisms linking vascular disease with depression.
      ,
      • Alexopoulos G.S.
      Mechanisms and treatment of late-life depression.
      ).
      Figure thumbnail gr1
      Figure 1Detrimental effects of cerebral microvascular dysfunction on the brain. Microvascular dysfunction may include increased blood-brain permeability (A) and impaired blood perfusion regulation, with disturbed neurovascular coupling (B) and impaired cerebral autoregulation (C) (
      • van Sloten T.T.
      • Sedaghat S.
      • Carnethon M.R.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral microvascular complications of type 2 diabetes: Stroke, cognitive dysfunction, and depression.
      ). Increased blood-brain permeability (A) leads to leakage of inflammatory proteins and cells and other plasma constituents into the perivascular space (
      • Wardlaw J.M.
      • Smith C.
      • Dichgans M.
      Small vessel disease: Mechanisms and clinical implications.
      ). Neurovascular coupling (B) involves a complex interaction between various cells (i.e., neuronal cells, astrocytes, endothelial cells, pericytes, and smooth muscle cells) and various mediators (
      • Wardlaw J.M.
      • Smith C.
      • Dichgans M.
      Small vessel disease: Mechanisms and clinical implications.
      ). Dysfunction of each of these components may contribute to disturbed neurovascular coupling. For instance, both endothelial and neuronal dysfunction may lead to lower release of endothelial- or neuronal-derived nitric oxide, leading to impaired vasodilatation (
      • Kisler K.
      • Nelson A.R.
      • Montagne A.
      • Zlokovic B.V.
      Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease.
      ). Cerebral autoregulation (C) is the ability of the cerebrovasculature to maintain a constant level of global brain perfusion despite varying arterial blood pressure (
      • Willie C.K.
      • Tzeng Y.C.
      • Fisher J.A.
      • Ainslie P.N.
      Integrative regulation of human brain blood flow.
      ). With impaired autoregulation, the normal autoregulation curve that expresses the relationship between cerebral blood flow and mean blood pressure (black curve) in panel (C) may become more linear and steeper, and perfusion may become pressure-dependent (red curve) in panel (C) (
      • Novak V.
      • Hajjar I.
      The relationship between blood pressure and cognitive function.
      ).
      Figure thumbnail gr2
      Figure 2Mechanistic pathway by which cerebral microvascular dysfunction may contribute to late-onset depression. Microvascular dysfunction–related increased blood-brain permeability leads to leakage of proteins and other plasma constituents into the perivascular space. This may directly damage neurons and is related to inflammatory and immune responses (
      • Wardlaw J.M.
      • Smith C.
      • Dichgans M.
      Small vessel disease: Mechanisms and clinical implications.
      ,
      • van Sloten T.T.
      • Sedaghat S.
      • Carnethon M.R.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral microvascular complications of type 2 diabetes: Stroke, cognitive dysfunction, and depression.
      ). Cerebral microvascular dysfunction also includes impaired blood flow regulation with impaired cerebral autoregulation and neurovascular coupling and disturbed capillary flow patterns (
      • Østergaard L.
      • Aamand R.
      • Gutiérrez-Jiménez E.
      • Ho Y.C.
      • Blicher J.U.
      • Madsen S.M.
      • et al.
      The capillary dysfunction hypothesis of Alzheimer’s disease.
      ). This can result in perfusion deficits, reduced oxygen extraction, and hypoxia. Hypoxia leads to activation of hypoxia-inducible transcription factors, which, in turn, triggers inflammation and expression of matrix metalloproteinases and proangiogenic factors (
      • Sweeney M.D.
      • Sagare A.P.
      • Zlokovic B.V.
      Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders.
      ). Matrix metalloproteinases damage endothelial tight junctions, contributing to increased blood-brain barrier permeability. Proangiogenetic factors, including vascular endothelial growth factor, also increase the permeability of the blood-brain barrier and stimulate angiogenesis. Angiogenesis is associated with formation of capillaries that are leaky and poorly perfused and that lack pericyte support (
      • Sweeney M.D.
      • Zhao Z.
      • Montagne A.
      • Nelson A.R.
      • Zlokovic B.V.
      Blood-brain barrier: From physiology to disease and back.
      ). Via these mechanisms, microvascular dysfunction can lead to local ischemia and hemorrhage and focal brain injury, ultimately leading to disturbed affective and cognitive processing and depression. BBB, blood-brain barrier.

      Evidence of Cerebral Microvascular Dysfunction in Depression

      A summary of studies in adults on the association between cerebral microvascular function and structure and depression is shown in Table 2, and these studies are discussed in the sections below. Most studies found an association between microvascular dysfunction and depression, although not all results are consistent. Most studies had a case-control design and included relatively small (N < 100) clinical samples of individuals with a current depressive episode.
      Table 2Altered Cerebral Microvascular Function and Structure in Individuals With Incident or Prevalent Depression as Compared With Individuals Without Depression: Summary of Findings in Humans
      Studies evaluated major depressive disorder according to DSM criteria (24–27,35–42,47–49,53,60–62,64,65), or presence of depressive symptoms based on questionnaires (35,40,44,46,52,53,59). The sample sizes of studies (N) were <50 (26,38,41,42,49,60,61,64,65), 50–100 (24,25,36,37,39,44,62), 100–500 (27,46–48,59), or >500 (35,40,52,53). Study designs included case-control (25–27,36–39,41,42,44,48,49,59–62,64,65) and cross-sectional (24,40) or longitudinal (35,46,52,53) cohorts. Population sources were clinical sample-based (25–27,36–39,41,42,44,46–49,60–62,64,65) and population-based (24,35,40,52,53,59). Studies included older adults (>60 years or older) only (24,35,38,40,42,47–49,53,59–62,64) or also included younger individuals (25–27,36,37,39,41,44,46,52). Of the studies investigating older individuals only, some excluded individuals with a depressive disorder before late life (38,47,48,62,65), whereas others did not (24,35,40,42,49,52,53,59–61,64).
      Manifestation of Altered Cerebral Microvascular Function and StructureTechnique(s)Findings in Individuals With Depression as Compared to Those Without
      Increased Blood-Brain Barrier PermeabilityQalb; neuropathologyIncreased blood-brain barrier permeability in cross-sectional studies (
      • Gudmundsson P.
      • Skoog I.
      • Waern M.
      • Blennow K.
      • Pálsson S.
      • Rosengren L.
      • Gustafson D.
      The relationship between cerebrospinal fluid biomarkers and depression in elderly women.
      ,
      • Bechter K.
      • Reiber H.
      • Herzog S.
      • Fuchs D.
      • Tumani H.
      • Maxeiner H.G.
      Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: Identification of subgroups with immune responses and blood-CSF barrier dysfunction.
      ,
      • Zachrisson O.C.
      • Balldin J.
      • Ekman R.
      • Naesh O.
      • Rosengren L.
      • Agren H.
      • Blennow K.
      No evident neuronal damage after electroconvulsive therapy.
      ,
      • Niklasson F.
      • Agren H.
      Brain energy metabolism and blood-brain barrier permeability in depressive patients: Analyses of creatine, creatinine, urate, and albumin in CSF and blood.
      ). No prospective data available.
      Reduced Cerebral VasoreactivityTCD; ASL; SPECTOne prospective study (
      • Direk N.
      • Koudstaal P.J.
      • Hofman A.
      • Ikram M.A.
      • Hoogendijk W.J.
      • Tiemeier H.
      Cerebral hemodynamics and incident depression: The Rotterdam Study.
      ) found that cerebral vasoreactivity increased the risk of depression. Most cross-sectional studies (
      • de Castro A.G.
      • Bajbouj M.
      • Schlattmann P.
      • Lemke H.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity in depressed patients without vascular risk factors.
      ,
      • Lemke H.
      • de Castro A.G.
      • Schlattmann P.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity over time-course - From major depressive episode to remission.
      ,
      • Matsuo K.
      • Onodera Y.
      • Hamamoto T.
      • Muraki K.
      • Kato N.
      • Kato T.
      Hypofrontality and microvascular dysregulation in remitted late-onset depression assessed by functional near-infrared spectroscopy.
      ,
      • Neu P.
      • Schlattmann P.
      • Schilling A.
      • Hartmann A.
      Cerebrovascular reactivity in major depression: A pilot study.
      ,
      • Tiemeier H.
      • Bakker S.L.
      • Hofman A.
      • Koudstaal P.J.
      • Breteler M.M.
      Cerebral haemodynamics and depression in the elderly.
      ,
      • Vakilian A.
      • Iranmanesh F.
      Assessment of cerebrovascular reactivity during major depression and after remission of disease.
      ), but not all (
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression.
      ), also found reduced cerebral vasoreactivity. Most of these studies determined vasoreactivity at the level of a large cerebral artery.
      Impaired Cerebral AutoregulationTCDOne cross-sectional study (
      • Luo M.Y.
      • Guo Z.N.
      • Qu Y.
      • Zhang P.
      • Wang Z.
      • Jin H.
      • et al.
      Compromised dynamic cerebral autoregulation in patients with depression.
      ) found impaired cerebral autoregulation. No prospective data available.
      Altered Resting Cerebral Blood FlowTCD; SPECT; ASL; PC-MRAIn two prospective studies (
      • Direk N.
      • Koudstaal P.J.
      • Hofman A.
      • Ikram M.A.
      • Hoogendijk W.J.
      • Tiemeier H.
      Cerebral hemodynamics and incident depression: The Rotterdam Study.
      ,
      • Alosco M.L.
      • Spitznagel M.B.
      • Cohen R.
      • Raz N.
      • Sweet L.H.
      • Josephson R.
      • et al.
      Reduced cerebral perfusion predicts greater depressive symptoms and cognitive dysfunction at a 1-year follow-up in patients with heart failure.
      ), lower cerebral blood flow velocity, an indirect measure of blood flow, was associated with incident depression. No prospective data available on direct measures of cerebral blood flow. Cross-sectional studies (
      • Wang J.
      • Li R.
      • Liu M.
      • Nie Z.
      • Jin L.
      • Lu Z.
      • Li Y.
      Impaired cerebral hemodynamics in late-onset depression: Computed tomography angiography, computed tomography perfusion, and magnetic resonance imaging evaluation.
      ,
      • Liao W.
      • Wang Z.
      • Zhang X.
      • Shu H.
      • Wang Z.
      • Liu D.
      • Zhang Z.
      Cerebral blood flow changes in remitted early- and late-onset depression patients.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression.
      ) found altered regional or global cerebral perfusion independently of cerebral atrophy.
      Retinal Microvascular ChangesDVA; fundoscopyOne prospective study (
      • Geraets A.F.J.
      • van Agtmaal M.J.M.
      • Stehouwer C.D.A.
      • Sörensen B.M.
      • Berendschot T.T.J.M.
      • Webers C.A.B.
      • et al.
      Association of markers of microvascular dysfunction with prevalent and incident depressive symptoms: The Maastricht Study.
      ) showed that lower flicker light–induced vasodilatation is associated with increased risk of depression, but another prospective study (
      • Ikram M.K.
      • Luijendijk H.J.
      • Hofman A.
      • de Jong P.T.
      • Breteler M.M.
      • Vingerling J.R.
      • Tiemeier H.
      Retinal vascular calibers and risk of late-life depression: The Rotterdam Study.
      ) did not find associations between microvascular diameters and depression.
      Cerebral Small Vessel DiseaseMRI: T1W, T2W, T2∗W, FLAIR; neuropathologyMeta-analyses (
      • Rensma S.P.
      • van Sloten T.T.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral small vessel disease and risk of incident stroke, dementia and depression, and all-cause mortality: A systematic review and meta-analysis.
      ,
      • Fang Y.
      • Qin T.
      • Liu W.
      • Ran L.
      • Yang Y.
      • Huang H.
      • et al.
      Cerebral small-vessel disease and risk of incidence of depression: A meta-analysis of longitudinal cohort studies.
      ,
      • van Agtmaal M.J.M.
      • Houben A.J.H.M.
      • Pouwer F.
      • Stehouwer C.D.A.
      • Schram M.T.
      Association of microvascular dysfunction with late-life depression: A systematic review and meta-analysis.
      ) found that cerebral small vessel disease features increase the risk of depression. Results are stronger for features in frontal and subcortical regions. Neuropathology studies (
      • Tsopelas C.
      • Stewart R.
      • Savva G.M.
      • Brayne C.
      • Ince P.
      • Thomas A.
      • et al.
      Neuropathological correlates of late-life depression in older people.
      ,
      • Thomas A.J.
      • O’Brien J.T.
      • Davis S.
      • Ballard C.
      • Barber R.
      • Kalaria R.N.
      • Perry R.H.
      Ischemic basis for deep white matter hyperintensities in major depression: A neuropathological study.
      ,
      • Thomas A.J.
      • Ferrier I.N.
      • Kalaria R.N.
      • Perry R.H.
      • Brown A.
      • O’Brien J.T.
      A neuropathological study of vascular factors in late-life depression.
      ,
      • Santos M.
      • Gold G.
      • Kövari E.
      • Herrmann F.R.
      • Hof P.R.
      • Bouras C.
      • Giannakopoulos P.
      Neuropathological analysis of lacunes and microvascular lesions in late-onset depression.
      ,
      • Santos M.
      • Gold G.
      • Kövari E.
      • Herrmann F.R.
      • Bozikas V.P.
      • Bouras C.
      • Giannakopoulos P.
      Differential impact of lacunes and microvascular lesions on poststroke depression.
      ,
      • O’Brien J.
      • Thomas A.
      • Ballard C.
      • Brown A.
      • Ferrier N.
      • Jaros E.
      • Perry R.
      Cognitive impairment in depression is not associated with neuropathologic evidence of increased vascular or Alzheimer-type pathology.
      ,
      • Lloyd A.J.
      • Grace J.B.
      • Jaros E.
      • Perry R.H.
      • Fairbairn A.F.
      • Swann A.G.
      • et al.
      Depression in late life, cognitive decline and white matter pathology in two clinico-pathologically investigated cases.
      ) have found inconsistent results.
      ASL, arterial spin labeling; DVA, dynamic vessel analysis; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; PC-MRA, phase-contrast magnetic resonance angiography; Qalb, cerebrospinal fluid/plasma albumin ratio; SPECT, single-photon emission computed tomography; TCD, transcranial doppler; T1W/T2W/T2∗W, Tx-weighted MR images.
      a Studies evaluated major depressive disorder according to DSM criteria (
      • Gudmundsson P.
      • Skoog I.
      • Waern M.
      • Blennow K.
      • Pálsson S.
      • Rosengren L.
      • Gustafson D.
      The relationship between cerebrospinal fluid biomarkers and depression in elderly women.
      ,
      • Bechter K.
      • Reiber H.
      • Herzog S.
      • Fuchs D.
      • Tumani H.
      • Maxeiner H.G.
      Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: Identification of subgroups with immune responses and blood-CSF barrier dysfunction.
      ,
      • Zachrisson O.C.
      • Balldin J.
      • Ekman R.
      • Naesh O.
      • Rosengren L.
      • Agren H.
      • Blennow K.
      No evident neuronal damage after electroconvulsive therapy.
      ,
      • Niklasson F.
      • Agren H.
      Brain energy metabolism and blood-brain barrier permeability in depressive patients: Analyses of creatine, creatinine, urate, and albumin in CSF and blood.
      ,
      • Direk N.
      • Koudstaal P.J.
      • Hofman A.
      • Ikram M.A.
      • Hoogendijk W.J.
      • Tiemeier H.
      Cerebral hemodynamics and incident depression: The Rotterdam Study.
      ,
      • de Castro A.G.
      • Bajbouj M.
      • Schlattmann P.
      • Lemke H.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity in depressed patients without vascular risk factors.
      ,
      • Lemke H.
      • de Castro A.G.
      • Schlattmann P.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity over time-course - From major depressive episode to remission.
      ,
      • Matsuo K.
      • Onodera Y.
      • Hamamoto T.
      • Muraki K.
      • Kato N.
      • Kato T.
      Hypofrontality and microvascular dysregulation in remitted late-onset depression assessed by functional near-infrared spectroscopy.
      ,
      • Neu P.
      • Schlattmann P.
      • Schilling A.
      • Hartmann A.
      Cerebrovascular reactivity in major depression: A pilot study.
      ,
      • Tiemeier H.
      • Bakker S.L.
      • Hofman A.
      • Koudstaal P.J.
      • Breteler M.M.
      Cerebral haemodynamics and depression in the elderly.
      ,
      • Vakilian A.
      • Iranmanesh F.
      Assessment of cerebrovascular reactivity during major depression and after remission of disease.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression.
      ,
      • Wang J.
      • Li R.
      • Liu M.
      • Nie Z.
      • Jin L.
      • Lu Z.
      • Li Y.
      Impaired cerebral hemodynamics in late-onset depression: Computed tomography angiography, computed tomography perfusion, and magnetic resonance imaging evaluation.
      ,
      • Liao W.
      • Wang Z.
      • Zhang X.
      • Shu H.
      • Wang Z.
      • Liu D.
      • Zhang Z.
      Cerebral blood flow changes in remitted early- and late-onset depression patients.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression.
      ,
      • Ikram M.K.
      • Luijendijk H.J.
      • Hofman A.
      • de Jong P.T.
      • Breteler M.M.
      • Vingerling J.R.
      • Tiemeier H.
      Retinal vascular calibers and risk of late-life depression: The Rotterdam Study.
      ,
      • Thomas A.J.
      • O’Brien J.T.
      • Davis S.
      • Ballard C.
      • Barber R.
      • Kalaria R.N.
      • Perry R.H.
      Ischemic basis for deep white matter hyperintensities in major depression: A neuropathological study.
      ,
      • Thomas A.J.
      • Ferrier I.N.
      • Kalaria R.N.
      • Perry R.H.
      • Brown A.
      • O’Brien J.T.
      A neuropathological study of vascular factors in late-life depression.
      ,
      • Santos M.
      • Gold G.
      • Kövari E.
      • Herrmann F.R.
      • Hof P.R.
      • Bouras C.
      • Giannakopoulos P.
      Neuropathological analysis of lacunes and microvascular lesions in late-onset depression.
      ,
      • O’Brien J.
      • Thomas A.
      • Ballard C.
      • Brown A.
      • Ferrier N.
      • Jaros E.
      • Perry R.
      Cognitive impairment in depression is not associated with neuropathologic evidence of increased vascular or Alzheimer-type pathology.
      ,
      • Lloyd A.J.
      • Grace J.B.
      • Jaros E.
      • Perry R.H.
      • Fairbairn A.F.
      • Swann A.G.
      • et al.
      Depression in late life, cognitive decline and white matter pathology in two clinico-pathologically investigated cases.
      ), or presence of depressive symptoms based on questionnaires (
      • Direk N.
      • Koudstaal P.J.
      • Hofman A.
      • Ikram M.A.
      • Hoogendijk W.J.
      • Tiemeier H.
      Cerebral hemodynamics and incident depression: The Rotterdam Study.
      ,
      • Tiemeier H.
      • Bakker S.L.
      • Hofman A.
      • Koudstaal P.J.
      • Breteler M.M.
      Cerebral haemodynamics and depression in the elderly.
      ,
      • Luo M.Y.
      • Guo Z.N.
      • Qu Y.
      • Zhang P.
      • Wang Z.
      • Jin H.
      • et al.
      Compromised dynamic cerebral autoregulation in patients with depression.
      ,
      • Alosco M.L.
      • Spitznagel M.B.
      • Cohen R.
      • Raz N.
      • Sweet L.H.
      • Josephson R.
      • et al.
      Reduced cerebral perfusion predicts greater depressive symptoms and cognitive dysfunction at a 1-year follow-up in patients with heart failure.
      ,
      • Geraets A.F.J.
      • van Agtmaal M.J.M.
      • Stehouwer C.D.A.
      • Sörensen B.M.
      • Berendschot T.T.J.M.
      • Webers C.A.B.
      • et al.
      Association of markers of microvascular dysfunction with prevalent and incident depressive symptoms: The Maastricht Study.
      ,
      • Ikram M.K.
      • Luijendijk H.J.
      • Hofman A.
      • de Jong P.T.
      • Breteler M.M.
      • Vingerling J.R.
      • Tiemeier H.
      Retinal vascular calibers and risk of late-life depression: The Rotterdam Study.
      ,
      • Tsopelas C.
      • Stewart R.
      • Savva G.M.
      • Brayne C.
      • Ince P.
      • Thomas A.
      • et al.
      Neuropathological correlates of late-life depression in older people.
      ). The sample sizes of studies (N) were <50 (
      • Zachrisson O.C.
      • Balldin J.
      • Ekman R.
      • Naesh O.
      • Rosengren L.
      • Agren H.
      • Blennow K.
      No evident neuronal damage after electroconvulsive therapy.
      ,
      • Matsuo K.
      • Onodera Y.
      • Hamamoto T.
      • Muraki K.
      • Kato N.
      • Kato T.
      Hypofrontality and microvascular dysregulation in remitted late-onset depression assessed by functional near-infrared spectroscopy.
      ,
      • Vakilian A.
      • Iranmanesh F.
      Assessment of cerebrovascular reactivity during major depression and after remission of disease.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression.
      ,
      • Thomas A.J.
      • O’Brien J.T.
      • Davis S.
      • Ballard C.
      • Barber R.
      • Kalaria R.N.
      • Perry R.H.
      Ischemic basis for deep white matter hyperintensities in major depression: A neuropathological study.
      ,
      • Thomas A.J.
      • Ferrier I.N.
      • Kalaria R.N.
      • Perry R.H.
      • Brown A.
      • O’Brien J.T.
      A neuropathological study of vascular factors in late-life depression.
      ,
      • O’Brien J.
      • Thomas A.
      • Ballard C.
      • Brown A.
      • Ferrier N.
      • Jaros E.
      • Perry R.
      Cognitive impairment in depression is not associated with neuropathologic evidence of increased vascular or Alzheimer-type pathology.
      ,
      • Lloyd A.J.
      • Grace J.B.
      • Jaros E.
      • Perry R.H.
      • Fairbairn A.F.
      • Swann A.G.
      • et al.
      Depression in late life, cognitive decline and white matter pathology in two clinico-pathologically investigated cases.
      ), 50–100 (
      • Gudmundsson P.
      • Skoog I.
      • Waern M.
      • Blennow K.
      • Pálsson S.
      • Rosengren L.
      • Gustafson D.
      The relationship between cerebrospinal fluid biomarkers and depression in elderly women.
      ,
      • Bechter K.
      • Reiber H.
      • Herzog S.
      • Fuchs D.
      • Tumani H.
      • Maxeiner H.G.
      Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: Identification of subgroups with immune responses and blood-CSF barrier dysfunction.
      ,
      • de Castro A.G.
      • Bajbouj M.
      • Schlattmann P.
      • Lemke H.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity in depressed patients without vascular risk factors.
      ,
      • Lemke H.
      • de Castro A.G.
      • Schlattmann P.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity over time-course - From major depressive episode to remission.
      ,
      • Neu P.
      • Schlattmann P.
      • Schilling A.
      • Hartmann A.
      Cerebrovascular reactivity in major depression: A pilot study.
      ,
      • Luo M.Y.
      • Guo Z.N.
      • Qu Y.
      • Zhang P.
      • Wang Z.
      • Jin H.
      • et al.
      Compromised dynamic cerebral autoregulation in patients with depression.
      ,
      • Santos M.
      • Gold G.
      • Kövari E.
      • Herrmann F.R.
      • Hof P.R.
      • Bouras C.
      • Giannakopoulos P.
      Neuropathological analysis of lacunes and microvascular lesions in late-onset depression.
      ), 100–500 (
      • Niklasson F.
      • Agren H.
      Brain energy metabolism and blood-brain barrier permeability in depressive patients: Analyses of creatine, creatinine, urate, and albumin in CSF and blood.
      ,
      • Alosco M.L.
      • Spitznagel M.B.
      • Cohen R.
      • Raz N.
      • Sweet L.H.
      • Josephson R.
      • et al.
      Reduced cerebral perfusion predicts greater depressive symptoms and cognitive dysfunction at a 1-year follow-up in patients with heart failure.
      ,
      • Wang J.
      • Li R.
      • Liu M.
      • Nie Z.
      • Jin L.
      • Lu Z.
      • Li Y.
      Impaired cerebral hemodynamics in late-onset depression: Computed tomography angiography, computed tomography perfusion, and magnetic resonance imaging evaluation.
      ,
      • Liao W.
      • Wang Z.
      • Zhang X.
      • Shu H.
      • Wang Z.
      • Liu D.
      • Zhang Z.
      Cerebral blood flow changes in remitted early- and late-onset depression patients.
      ,
      • Tsopelas C.
      • Stewart R.
      • Savva G.M.
      • Brayne C.
      • Ince P.
      • Thomas A.
      • et al.
      Neuropathological correlates of late-life depression in older people.
      ), or >500 (
      • Direk N.
      • Koudstaal P.J.
      • Hofman A.
      • Ikram M.A.
      • Hoogendijk W.J.
      • Tiemeier H.
      Cerebral hemodynamics and incident depression: The Rotterdam Study.
      ,
      • Tiemeier H.
      • Bakker S.L.
      • Hofman A.
      • Koudstaal P.J.
      • Breteler M.M.
      Cerebral haemodynamics and depression in the elderly.
      ,
      • Geraets A.F.J.
      • van Agtmaal M.J.M.
      • Stehouwer C.D.A.
      • Sörensen B.M.
      • Berendschot T.T.J.M.
      • Webers C.A.B.
      • et al.
      Association of markers of microvascular dysfunction with prevalent and incident depressive symptoms: The Maastricht Study.
      ,
      • Ikram M.K.
      • Luijendijk H.J.
      • Hofman A.
      • de Jong P.T.
      • Breteler M.M.
      • Vingerling J.R.
      • Tiemeier H.
      Retinal vascular calibers and risk of late-life depression: The Rotterdam Study.
      ). Study designs included case-control (
      • Bechter K.
      • Reiber H.
      • Herzog S.
      • Fuchs D.
      • Tumani H.
      • Maxeiner H.G.
      Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: Identification of subgroups with immune responses and blood-CSF barrier dysfunction.
      ,
      • Zachrisson O.C.
      • Balldin J.
      • Ekman R.
      • Naesh O.
      • Rosengren L.
      • Agren H.
      • Blennow K.
      No evident neuronal damage after electroconvulsive therapy.
      ,
      • Niklasson F.
      • Agren H.
      Brain energy metabolism and blood-brain barrier permeability in depressive patients: Analyses of creatine, creatinine, urate, and albumin in CSF and blood.
      ,
      • de Castro A.G.
      • Bajbouj M.
      • Schlattmann P.
      • Lemke H.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity in depressed patients without vascular risk factors.
      ,
      • Lemke H.
      • de Castro A.G.
      • Schlattmann P.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity over time-course - From major depressive episode to remission.
      ,
      • Matsuo K.
      • Onodera Y.
      • Hamamoto T.
      • Muraki K.
      • Kato N.
      • Kato T.
      Hypofrontality and microvascular dysregulation in remitted late-onset depression assessed by functional near-infrared spectroscopy.
      ,
      • Neu P.
      • Schlattmann P.
      • Schilling A.
      • Hartmann A.
      Cerebrovascular reactivity in major depression: A pilot study.
      ,
      • Vakilian A.
      • Iranmanesh F.
      Assessment of cerebrovascular reactivity during major depression and after remission of disease.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression.
      ,
      • Luo M.Y.
      • Guo Z.N.
      • Qu Y.
      • Zhang P.
      • Wang Z.
      • Jin H.
      • et al.
      Compromised dynamic cerebral autoregulation in patients with depression.
      ,
      • Liao W.
      • Wang Z.
      • Zhang X.
      • Shu H.
      • Wang Z.
      • Liu D.
      • Zhang Z.
      Cerebral blood flow changes in remitted early- and late-onset depression patients.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression.
      ,
      • Tsopelas C.
      • Stewart R.
      • Savva G.M.
      • Brayne C.
      • Ince P.
      • Thomas A.
      • et al.
      Neuropathological correlates of late-life depression in older people.
      ,
      • Thomas A.J.
      • O’Brien J.T.
      • Davis S.
      • Ballard C.
      • Barber R.
      • Kalaria R.N.
      • Perry R.H.
      Ischemic basis for deep white matter hyperintensities in major depression: A neuropathological study.
      ,
      • Thomas A.J.
      • Ferrier I.N.
      • Kalaria R.N.
      • Perry R.H.
      • Brown A.
      • O’Brien J.T.
      A neuropathological study of vascular factors in late-life depression.
      ,
      • Santos M.
      • Gold G.
      • Kövari E.
      • Herrmann F.R.
      • Hof P.R.
      • Bouras C.
      • Giannakopoulos P.
      Neuropathological analysis of lacunes and microvascular lesions in late-onset depression.
      ,
      • O’Brien J.
      • Thomas A.
      • Ballard C.
      • Brown A.
      • Ferrier N.
      • Jaros E.
      • Perry R.
      Cognitive impairment in depression is not associated with neuropathologic evidence of increased vascular or Alzheimer-type pathology.
      ,
      • Lloyd A.J.
      • Grace J.B.
      • Jaros E.
      • Perry R.H.
      • Fairbairn A.F.
      • Swann A.G.
      • et al.
      Depression in late life, cognitive decline and white matter pathology in two clinico-pathologically investigated cases.
      ) and cross-sectional (
      • Gudmundsson P.
      • Skoog I.
      • Waern M.
      • Blennow K.
      • Pálsson S.
      • Rosengren L.
      • Gustafson D.
      The relationship between cerebrospinal fluid biomarkers and depression in elderly women.
      ,
      • Tiemeier H.
      • Bakker S.L.
      • Hofman A.
      • Koudstaal P.J.
      • Breteler M.M.
      Cerebral haemodynamics and depression in the elderly.
      ) or longitudinal (
      • Direk N.
      • Koudstaal P.J.
      • Hofman A.
      • Ikram M.A.
      • Hoogendijk W.J.
      • Tiemeier H.
      Cerebral hemodynamics and incident depression: The Rotterdam Study.
      ,
      • Alosco M.L.
      • Spitznagel M.B.
      • Cohen R.
      • Raz N.
      • Sweet L.H.
      • Josephson R.
      • et al.
      Reduced cerebral perfusion predicts greater depressive symptoms and cognitive dysfunction at a 1-year follow-up in patients with heart failure.
      ,
      • Geraets A.F.J.
      • van Agtmaal M.J.M.
      • Stehouwer C.D.A.
      • Sörensen B.M.
      • Berendschot T.T.J.M.
      • Webers C.A.B.
      • et al.
      Association of markers of microvascular dysfunction with prevalent and incident depressive symptoms: The Maastricht Study.
      ,
      • Ikram M.K.
      • Luijendijk H.J.
      • Hofman A.
      • de Jong P.T.
      • Breteler M.M.
      • Vingerling J.R.
      • Tiemeier H.
      Retinal vascular calibers and risk of late-life depression: The Rotterdam Study.
      ) cohorts. Population sources were clinical sample-based (
      • Bechter K.
      • Reiber H.
      • Herzog S.
      • Fuchs D.
      • Tumani H.
      • Maxeiner H.G.
      Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: Identification of subgroups with immune responses and blood-CSF barrier dysfunction.
      ,
      • Zachrisson O.C.
      • Balldin J.
      • Ekman R.
      • Naesh O.
      • Rosengren L.
      • Agren H.
      • Blennow K.
      No evident neuronal damage after electroconvulsive therapy.
      ,
      • Niklasson F.
      • Agren H.
      Brain energy metabolism and blood-brain barrier permeability in depressive patients: Analyses of creatine, creatinine, urate, and albumin in CSF and blood.
      ,
      • de Castro A.G.
      • Bajbouj M.
      • Schlattmann P.
      • Lemke H.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity in depressed patients without vascular risk factors.
      ,
      • Lemke H.
      • de Castro A.G.
      • Schlattmann P.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity over time-course - From major depressive episode to remission.
      ,
      • Matsuo K.
      • Onodera Y.
      • Hamamoto T.
      • Muraki K.
      • Kato N.
      • Kato T.
      Hypofrontality and microvascular dysregulation in remitted late-onset depression assessed by functional near-infrared spectroscopy.
      ,
      • Neu P.
      • Schlattmann P.
      • Schilling A.
      • Hartmann A.
      Cerebrovascular reactivity in major depression: A pilot study.
      ,
      • Vakilian A.
      • Iranmanesh F.
      Assessment of cerebrovascular reactivity during major depression and after remission of disease.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression.
      ,
      • Luo M.Y.
      • Guo Z.N.
      • Qu Y.
      • Zhang P.
      • Wang Z.
      • Jin H.
      • et al.
      Compromised dynamic cerebral autoregulation in patients with depression.
      ,
      • Alosco M.L.
      • Spitznagel M.B.
      • Cohen R.
      • Raz N.
      • Sweet L.H.
      • Josephson R.
      • et al.
      Reduced cerebral perfusion predicts greater depressive symptoms and cognitive dysfunction at a 1-year follow-up in patients with heart failure.
      ,
      • Wang J.
      • Li R.
      • Liu M.
      • Nie Z.
      • Jin L.
      • Lu Z.
      • Li Y.
      Impaired cerebral hemodynamics in late-onset depression: Computed tomography angiography, computed tomography perfusion, and magnetic resonance imaging evaluation.
      ,
      • Liao W.
      • Wang Z.
      • Zhang X.
      • Shu H.
      • Wang Z.
      • Liu D.
      • Zhang Z.
      Cerebral blood flow changes in remitted early- and late-onset depression patients.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression.
      ,
      • Thomas A.J.
      • O’Brien J.T.
      • Davis S.
      • Ballard C.
      • Barber R.
      • Kalaria R.N.
      • Perry R.H.
      Ischemic basis for deep white matter hyperintensities in major depression: A neuropathological study.
      ,
      • Thomas A.J.
      • Ferrier I.N.
      • Kalaria R.N.
      • Perry R.H.
      • Brown A.
      • O’Brien J.T.
      A neuropathological study of vascular factors in late-life depression.
      ,
      • Santos M.
      • Gold G.
      • Kövari E.
      • Herrmann F.R.
      • Hof P.R.
      • Bouras C.
      • Giannakopoulos P.
      Neuropathological analysis of lacunes and microvascular lesions in late-onset depression.
      ,
      • O’Brien J.
      • Thomas A.
      • Ballard C.
      • Brown A.
      • Ferrier N.
      • Jaros E.
      • Perry R.
      Cognitive impairment in depression is not associated with neuropathologic evidence of increased vascular or Alzheimer-type pathology.
      ,
      • Lloyd A.J.
      • Grace J.B.
      • Jaros E.
      • Perry R.H.
      • Fairbairn A.F.
      • Swann A.G.
      • et al.
      Depression in late life, cognitive decline and white matter pathology in two clinico-pathologically investigated cases.
      ) and population-based (
      • Gudmundsson P.
      • Skoog I.
      • Waern M.
      • Blennow K.
      • Pálsson S.
      • Rosengren L.
      • Gustafson D.
      The relationship between cerebrospinal fluid biomarkers and depression in elderly women.
      ,
      • Direk N.
      • Koudstaal P.J.
      • Hofman A.
      • Ikram M.A.
      • Hoogendijk W.J.
      • Tiemeier H.
      Cerebral hemodynamics and incident depression: The Rotterdam Study.
      ,
      • Tiemeier H.
      • Bakker S.L.
      • Hofman A.
      • Koudstaal P.J.
      • Breteler M.M.
      Cerebral haemodynamics and depression in the elderly.
      ,
      • Geraets A.F.J.
      • van Agtmaal M.J.M.
      • Stehouwer C.D.A.
      • Sörensen B.M.
      • Berendschot T.T.J.M.
      • Webers C.A.B.
      • et al.
      Association of markers of microvascular dysfunction with prevalent and incident depressive symptoms: The Maastricht Study.
      ,
      • Ikram M.K.
      • Luijendijk H.J.
      • Hofman A.
      • de Jong P.T.
      • Breteler M.M.
      • Vingerling J.R.
      • Tiemeier H.
      Retinal vascular calibers and risk of late-life depression: The Rotterdam Study.
      ,
      • Tsopelas C.
      • Stewart R.
      • Savva G.M.
      • Brayne C.
      • Ince P.
      • Thomas A.
      • et al.
      Neuropathological correlates of late-life depression in older people.
      ). Studies included older adults (>60 years or older) only (
      • Gudmundsson P.
      • Skoog I.
      • Waern M.
      • Blennow K.
      • Pálsson S.
      • Rosengren L.
      • Gustafson D.
      The relationship between cerebrospinal fluid biomarkers and depression in elderly women.
      ,
      • Direk N.
      • Koudstaal P.J.
      • Hofman A.
      • Ikram M.A.
      • Hoogendijk W.J.
      • Tiemeier H.
      Cerebral hemodynamics and incident depression: The Rotterdam Study.
      ,
      • Matsuo K.
      • Onodera Y.
      • Hamamoto T.
      • Muraki K.
      • Kato N.
      • Kato T.
      Hypofrontality and microvascular dysregulation in remitted late-onset depression assessed by functional near-infrared spectroscopy.
      ,
      • Tiemeier H.
      • Bakker S.L.
      • Hofman A.
      • Koudstaal P.J.
      • Breteler M.M.
      Cerebral haemodynamics and depression in the elderly.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression.
      ,
      • Wang J.
      • Li R.
      • Liu M.
      • Nie Z.
      • Jin L.
      • Lu Z.
      • Li Y.
      Impaired cerebral hemodynamics in late-onset depression: Computed tomography angiography, computed tomography perfusion, and magnetic resonance imaging evaluation.
      ,
      • Liao W.
      • Wang Z.
      • Zhang X.
      • Shu H.
      • Wang Z.
      • Liu D.
      • Zhang Z.
      Cerebral blood flow changes in remitted early- and late-onset depression patients.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression.
      ,
      • Ikram M.K.
      • Luijendijk H.J.
      • Hofman A.
      • de Jong P.T.
      • Breteler M.M.
      • Vingerling J.R.
      • Tiemeier H.
      Retinal vascular calibers and risk of late-life depression: The Rotterdam Study.
      ,
      • Tsopelas C.
      • Stewart R.
      • Savva G.M.
      • Brayne C.
      • Ince P.
      • Thomas A.
      • et al.
      Neuropathological correlates of late-life depression in older people.
      ,
      • Thomas A.J.
      • O’Brien J.T.
      • Davis S.
      • Ballard C.
      • Barber R.
      • Kalaria R.N.
      • Perry R.H.
      Ischemic basis for deep white matter hyperintensities in major depression: A neuropathological study.
      ,
      • Thomas A.J.
      • Ferrier I.N.
      • Kalaria R.N.
      • Perry R.H.
      • Brown A.
      • O’Brien J.T.
      A neuropathological study of vascular factors in late-life depression.
      ,
      • Santos M.
      • Gold G.
      • Kövari E.
      • Herrmann F.R.
      • Hof P.R.
      • Bouras C.
      • Giannakopoulos P.
      Neuropathological analysis of lacunes and microvascular lesions in late-onset depression.
      ,
      • O’Brien J.
      • Thomas A.
      • Ballard C.
      • Brown A.
      • Ferrier N.
      • Jaros E.
      • Perry R.
      Cognitive impairment in depression is not associated with neuropathologic evidence of increased vascular or Alzheimer-type pathology.
      ) or also included younger individuals (
      • Bechter K.
      • Reiber H.
      • Herzog S.
      • Fuchs D.
      • Tumani H.
      • Maxeiner H.G.
      Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: Identification of subgroups with immune responses and blood-CSF barrier dysfunction.
      ,
      • Zachrisson O.C.
      • Balldin J.
      • Ekman R.
      • Naesh O.
      • Rosengren L.
      • Agren H.
      • Blennow K.
      No evident neuronal damage after electroconvulsive therapy.
      ,
      • Niklasson F.
      • Agren H.
      Brain energy metabolism and blood-brain barrier permeability in depressive patients: Analyses of creatine, creatinine, urate, and albumin in CSF and blood.
      ,
      • de Castro A.G.
      • Bajbouj M.
      • Schlattmann P.
      • Lemke H.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity in depressed patients without vascular risk factors.
      ,
      • Lemke H.
      • de Castro A.G.
      • Schlattmann P.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity over time-course - From major depressive episode to remission.
      ,
      • Neu P.
      • Schlattmann P.
      • Schilling A.
      • Hartmann A.
      Cerebrovascular reactivity in major depression: A pilot study.
      ,
      • Vakilian A.
      • Iranmanesh F.
      Assessment of cerebrovascular reactivity during major depression and after remission of disease.
      ,
      • Luo M.Y.
      • Guo Z.N.
      • Qu Y.
      • Zhang P.
      • Wang Z.
      • Jin H.
      • et al.
      Compromised dynamic cerebral autoregulation in patients with depression.
      ,
      • Alosco M.L.
      • Spitznagel M.B.
      • Cohen R.
      • Raz N.
      • Sweet L.H.
      • Josephson R.
      • et al.
      Reduced cerebral perfusion predicts greater depressive symptoms and cognitive dysfunction at a 1-year follow-up in patients with heart failure.
      ,
      • Geraets A.F.J.
      • van Agtmaal M.J.M.
      • Stehouwer C.D.A.
      • Sörensen B.M.
      • Berendschot T.T.J.M.
      • Webers C.A.B.
      • et al.
      Association of markers of microvascular dysfunction with prevalent and incident depressive symptoms: The Maastricht Study.
      ). Of the studies investigating older individuals only, some excluded individuals with a depressive disorder before late life (
      • Matsuo K.
      • Onodera Y.
      • Hamamoto T.
      • Muraki K.
      • Kato N.
      • Kato T.
      Hypofrontality and microvascular dysregulation in remitted late-onset depression assessed by functional near-infrared spectroscopy.
      ,
      • Wang J.
      • Li R.
      • Liu M.
      • Nie Z.
      • Jin L.
      • Lu Z.
      • Li Y.
      Impaired cerebral hemodynamics in late-onset depression: Computed tomography angiography, computed tomography perfusion, and magnetic resonance imaging evaluation.
      ,
      • Liao W.
      • Wang Z.
      • Zhang X.
      • Shu H.
      • Wang Z.
      • Liu D.
      • Zhang Z.
      Cerebral blood flow changes in remitted early- and late-onset depression patients.
      ,
      • Santos M.
      • Gold G.
      • Kövari E.
      • Herrmann F.R.
      • Hof P.R.
      • Bouras C.
      • Giannakopoulos P.
      Neuropathological analysis of lacunes and microvascular lesions in late-onset depression.
      ,
      • Lloyd A.J.
      • Grace J.B.
      • Jaros E.
      • Perry R.H.
      • Fairbairn A.F.
      • Swann A.G.
      • et al.
      Depression in late life, cognitive decline and white matter pathology in two clinico-pathologically investigated cases.
      ), whereas others did not (
      • Gudmundsson P.
      • Skoog I.
      • Waern M.
      • Blennow K.
      • Pálsson S.
      • Rosengren L.
      • Gustafson D.
      The relationship between cerebrospinal fluid biomarkers and depression in elderly women.
      ,
      • Direk N.
      • Koudstaal P.J.
      • Hofman A.
      • Ikram M.A.
      • Hoogendijk W.J.
      • Tiemeier H.
      Cerebral hemodynamics and incident depression: The Rotterdam Study.
      ,
      • Tiemeier H.
      • Bakker S.L.
      • Hofman A.
      • Koudstaal P.J.
      • Breteler M.M.
      Cerebral haemodynamics and depression in the elderly.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression.
      ,
      • Geraets A.F.J.
      • van Agtmaal M.J.M.
      • Stehouwer C.D.A.
      • Sörensen B.M.
      • Berendschot T.T.J.M.
      • Webers C.A.B.
      • et al.
      Association of markers of microvascular dysfunction with prevalent and incident depressive symptoms: The Maastricht Study.
      ,
      • Ikram M.K.
      • Luijendijk H.J.
      • Hofman A.
      • de Jong P.T.
      • Breteler M.M.
      • Vingerling J.R.
      • Tiemeier H.
      Retinal vascular calibers and risk of late-life depression: The Rotterdam Study.
      ,
      • Tsopelas C.
      • Stewart R.
      • Savva G.M.
      • Brayne C.
      • Ince P.
      • Thomas A.
      • et al.
      Neuropathological correlates of late-life depression in older people.
      ,
      • Thomas A.J.
      • O’Brien J.T.
      • Davis S.
      • Ballard C.
      • Barber R.
      • Kalaria R.N.
      • Perry R.H.
      Ischemic basis for deep white matter hyperintensities in major depression: A neuropathological study.
      ,
      • Thomas A.J.
      • Ferrier I.N.
      • Kalaria R.N.
      • Perry R.H.
      • Brown A.
      • O’Brien J.T.
      A neuropathological study of vascular factors in late-life depression.
      ,
      • O’Brien J.
      • Thomas A.
      • Ballard C.
      • Brown A.
      • Ferrier N.
      • Jaros E.
      • Perry R.
      Cognitive impairment in depression is not associated with neuropathologic evidence of increased vascular or Alzheimer-type pathology.
      ).

      Blood-Brain Barrier Permeability

      Evidence for the presence of increased blood-brain barrier permeability in depression in humans comes mostly from biochemical studies that assessed the ratio of cerebrospinal fluid albumin to serum albumin level, which is known as the albumin quotient (for explanation of albumin quotient, see Table 1). One case-control study (
      • Gudmundsson P.
      • Skoog I.
      • Waern M.
      • Blennow K.
      • Pálsson S.
      • Rosengren L.
      • Gustafson D.
      The relationship between cerebrospinal fluid biomarkers and depression in elderly women.
      ) found a higher albumin quotient among older patients with depression than among older individuals without depression. Other studies among patients with depression found a higher albumin quotient in a subset of these patients than previously reported reference values in the general population (
      • Bechter K.
      • Reiber H.
      • Herzog S.
      • Fuchs D.
      • Tumani H.
      • Maxeiner H.G.
      Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: Identification of subgroups with immune responses and blood-CSF barrier dysfunction.
      ,
      • Zachrisson O.C.
      • Balldin J.
      • Ekman R.
      • Naesh O.
      • Rosengren L.
      • Agren H.
      • Blennow K.
      No evident neuronal damage after electroconvulsive therapy.
      ), and a higher albumin quotient was associated with suicidality (
      • Niklasson F.
      • Agren H.
      Brain energy metabolism and blood-brain barrier permeability in depressive patients: Analyses of creatine, creatinine, urate, and albumin in CSF and blood.
      ). Additionally, postmortem studies have found evidence of structural alterations of the blood-brain barrier in depression. This includes an increased endothelial expression of intercellular adhesion molecule-1 (
      • Thomas A.J.
      • Perry R.
      • Kalaria R.N.
      • Oakley A.
      • McMeekin W.
      • O’Brien J.T.
      Neuropathological evidence for ischemia in the white matter of the dorsolateral prefrontal cortex in late-life depression.
      ,
      • Thomas A.J.
      • Ferrier I.N.
      • Kalaria R.N.
      • Woodward S.A.
      • Ballard C.
      • Oakley A.
      • et al.
      Elevation in late-life depression of intercellular adhesion molecule-1 expression in the dorsolateral prefrontal cortex.
      ,
      • Miguel-Hidalgo J.J.
      • Overholser J.C.
      • Jurjus G.J.
      • Meltzer H.Y.
      • Dieter L.
      • Konick L.
      • et al.
      Vascular and extravascular immunoreactivity for intercellular adhesion molecule 1 in the orbitofrontal cortex of subjects with major depression: Age-dependent changes.
      ), a marker of microvascular endothelial dysfunction, and reduced coverage of the endothelium by astrocyte end feet in the prefrontal cortex (
      • Rajkowska G.
      • Hughes J.
      • Stockmeier C.A.
      • Javier Miguel-Hidalgo J.
      • Maciag D.
      Coverage of blood vessels by astrocytic endfeet is reduced in major depressive disorder.
      ). Other studies found an increased expression of endothelial protein claudin-5, a key tight-junction protein in the nucleus accumbens (
      • Menard C.
      • Pfau M.L.
      • Hodes G.E.
      • Kana V.
      • Wang V.X.
      • Bouchard S.
      • et al.
      Social stress induces neurovascular pathology promoting depression.
      ,
      • Dudek K.A.
      • Dion-Albert L.
      • Lebel M.
      • LeClair K.
      • Labrecque S.
      • Tuck E.
      • et al.
      Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression.
      ). The prefrontal cortex and nucleus accumbens are crucial regions within the brain’s reward circuitry, and their function is impaired in individuals with major depression (
      • Russo S.J.
      • Nestler E.J.
      The brain reward circuitry in mood disorders.
      ). Reduced expression of claudin-5 has also been found in an animal model of depression, and this was related to greater blood-brain permeability in this model (
      • Menard C.
      • Pfau M.L.
      • Hodes G.E.
      • Kana V.
      • Wang V.X.
      • Bouchard S.
      • et al.
      Social stress induces neurovascular pathology promoting depression.
      ).

      Cerebrovascular Reactivity, Cerebral Autoregulation, and Resting Cerebral Blood Flow

      Microvascular dysfunction may manifest as disrupted cerebrovascular reactivity (for explanation of cerebrovascular reactivity, see Table 1). One prospective, population-based study showed that lower cerebrovascular reactivity was associated with higher risk of depression in older individuals (
      • Direk N.
      • Koudstaal P.J.
      • Hofman A.
      • Ikram M.A.
      • Hoogendijk W.J.
      • Tiemeier H.
      Cerebral hemodynamics and incident depression: The Rotterdam Study.
      ). Additionally, most cross-sectional studies (
      • de Castro A.G.
      • Bajbouj M.
      • Schlattmann P.
      • Lemke H.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity in depressed patients without vascular risk factors.
      ,
      • Lemke H.
      • de Castro A.G.
      • Schlattmann P.
      • Heuser I.
      • Neu P.
      Cerebrovascular reactivity over time-course - From major depressive episode to remission.
      ,
      • Matsuo K.
      • Onodera Y.
      • Hamamoto T.
      • Muraki K.
      • Kato N.
      • Kato T.
      Hypofrontality and microvascular dysregulation in remitted late-onset depression assessed by functional near-infrared spectroscopy.
      ,
      • Neu P.
      • Schlattmann P.
      • Schilling A.
      • Hartmann A.
      Cerebrovascular reactivity in major depression: A pilot study.
      ,
      • Tiemeier H.
      • Bakker S.L.
      • Hofman A.
      • Koudstaal P.J.
      • Breteler M.M.
      Cerebral haemodynamics and depression in the elderly.
      ,
      • Vakilian A.
      • Iranmanesh F.
      Assessment of cerebrovascular reactivity during major depression and after remission of disease.
      ), but not all (
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression.
      ), found lower cerebrovascular reactivity in individuals with depression than in individuals without depression. However, most of these studies measured cerebrovascular reactivity at the level of a large artery with use of Doppler ultrasound, and only some studies (
      • Matsuo K.
      • Onodera Y.
      • Hamamoto T.
      • Muraki K.
      • Kato N.
      • Kato T.
      Hypofrontality and microvascular dysregulation in remitted late-onset depression assessed by functional near-infrared spectroscopy.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression.
      ) measured cerebrovascular reactivity at the tissue level with use of magnetic resonance imaging or single-photon emission computed tomography. The interpretation of vasoreactivity measured in a large artery is difficult because it may reflect the function not only of arterioles and capillaries but also of larger cerebral arteries (
      • Thrippleton M.J.
      • Backes W.H.
      • Sourbron S.
      • Ingrisch M.
      • van Osch M.J.P.
      • Dichgans M.
      • et al.
      Quantifying blood-brain barrier leakage in small vessel disease: Review and consensus recommendations.
      ).
      Microvascular dysfunction might also contribute to altered cerebral autoregulation (for explanation of cerebral autoregulation, see Table 1). However, data on cerebral autoregulation in depression are scarce. Altered cerebral autoregulation was identified in a recent small cross-sectional study (
      • Luo M.Y.
      • Guo Z.N.
      • Qu Y.
      • Zhang P.
      • Wang Z.
      • Jin H.
      • et al.
      Compromised dynamic cerebral autoregulation in patients with depression.
      ), but replication of this finding is needed.
      Altered resting cerebral blood flow or blood flow velocity may be another manifestation of cerebral microvascular dysfunction. However, the interpretation of resting cerebral blood flow is complex, because reduced resting cerebral blood flow might be a cause of tissue damage or a consequence (i.e., reflect loss of viable tissue), or both. Lower cerebral blood flow velocity assessed at the level of large cerebral arteries with Doppler ultrasound, which may be related to lower global cerebral perfusion (
      • Miyazawa T.
      • Shibata S.
      • Nagai K.
      • Hirasawa A.
      • Kobayashi Y.
      • Koshiba H.
      • Kozaki K.
      Relationship between cerebral blood flow estimated by transcranial Doppler ultrasound and single-photon emission computed tomography in elderly people with dementia.
      ), was associated with higher risk of incident depressive symptoms in individuals with heart failure (
      • Alosco M.L.
      • Spitznagel M.B.
      • Cohen R.
      • Raz N.
      • Sweet L.H.
      • Josephson R.
      • et al.
      Reduced cerebral perfusion predicts greater depressive symptoms and cognitive dysfunction at a 1-year follow-up in patients with heart failure.
      ) and with incident depression in a large population-based study (
      • Direk N.
      • Koudstaal P.J.
      • Hofman A.
      • Ikram M.A.
      • Hoogendijk W.J.
      • Tiemeier H.
      Cerebral hemodynamics and incident depression: The Rotterdam Study.
      ). In addition, cross-sectional studies in older individuals with depression have found altered global (measured at the level of large arteries) or regional (at the tissue level) cerebral perfusion, independent of cerebral atrophy (
      • Wang J.
      • Li R.
      • Liu M.
      • Nie Z.
      • Jin L.
      • Lu Z.
      • Li Y.
      Impaired cerebral hemodynamics in late-onset depression: Computed tomography angiography, computed tomography perfusion, and magnetic resonance imaging evaluation.
      ,
      • Liao W.
      • Wang Z.
      • Zhang X.
      • Shu H.
      • Wang Z.
      • Liu D.
      • Zhang Z.
      Cerebral blood flow changes in remitted early- and late-onset depression patients.
      ,
      • Abi Zeid Daou M.
      • Boyd B.D.
      • Donahue M.J.
      • Albert K.
      • Taylor W.D.
      Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression.
      ). In one study, regional cerebral perfusion was altered to a greater extent in individuals with late-onset depression (defined in that study as the first onset of the episode after the age of 60 years), compared with individuals with early-onset depression and individuals without any depression, and altered cerebral perfusion was associated with worse cognitive performance in these individuals (
      • Liao W.
      • Wang Z.
      • Zhang X.
      • Shu H.
      • Wang Z.
      • Liu D.
      • Zhang Z.
      Cerebral blood flow changes in remitted early- and late-onset depression patients.
      ).

      Retinal Microvascular Changes

      The retina offers a unique opportunity to study microvascular changes in the brain because it allows direct and reproducible visualization of a microvascular bed that shares anatomical and physiological similarities with the cerebral microvasculature (
      • Cheung C.Y.
      • Ikram M.K.
      • Chen C.
      • Wong T.Y.
      Imaging retina to study dementia and stroke.
      ,
      • Nguyen T.T.
      • Kreis A.J.
      • Kawasaki R.
      • Wang J.J.
      • Seifert B.U.
      • Vilser W.
      • et al.
      Reproducibility of the retinal vascular response to flicker light in Asians.
      ). To date, only two studies (
      • Geraets A.F.J.
      • van Agtmaal M.J.M.
      • Stehouwer C.D.A.
      • Sörensen B.M.
      • Berendschot T.T.J.M.
      • Webers C.A.B.
      • et al.
      Association of markers of microvascular dysfunction with prevalent and incident depressive symptoms: The Maastricht Study.
      ,
      • Ikram M.K.
      • Luijendijk H.J.
      • Hofman A.
      • de Jong P.T.
      • Breteler M.M.
      • Vingerling J.R.
      • Tiemeier H.
      Retinal vascular calibers and risk of late-life depression: The Rotterdam Study.
      ), both population based, evaluated the association between measures of the retinal microvasculature and incident depressive symptoms, but they had inconsistent findings. One study found that a reduced flicker light–induced retinal arteriolar dilatation response, indicating worse microvascular function, was associated with a higher incidence of depressive symptoms (
      • Geraets A.F.J.
      • van Agtmaal M.J.M.
      • Stehouwer C.D.A.
      • Sörensen B.M.
      • Berendschot T.T.J.M.
      • Webers C.A.B.
      • et al.
      Association of markers of microvascular dysfunction with prevalent and incident depressive symptoms: The Maastricht Study.
      ). Another study evaluated the association between retinal arteriolar and venular diameters and incident depression but did not find a statistically significant association (
      • Ikram M.K.
      • Luijendijk H.J.
      • Hofman A.
      • de Jong P.T.
      • Breteler M.M.
      • Vingerling J.R.
      • Tiemeier H.
      Retinal vascular calibers and risk of late-life depression: The Rotterdam Study.
      ).

      Features of Cerebral Small Vessel Disease

      Cerebral microvascular dysfunction can also manifest itself as features of cerebral small vessel disease, which include white matter hyperintensities and lacunes of presumed vascular origin, cerebral microbleeds, perivascular spaces, total cerebral atrophy, and microinfarcts (
      • Wardlaw J.M.
      • Smith E.E.
      • Biessels G.J.
      • Cordonnier C.
      • Fazekas F.
      • Frayne R.
      • et al.
      Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration.
      ). These features are indirect or late-stage markers of small vessel abnormalities because they reflect brain parenchymal damage potentially related to various small vessel changes. Recent meta-analyses (
      • Rensma S.P.
      • van Sloten T.T.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral small vessel disease and risk of incident stroke, dementia and depression, and all-cause mortality: A systematic review and meta-analysis.
      ,
      • Fang Y.
      • Qin T.
      • Liu W.
      • Ran L.
      • Yang Y.
      • Huang H.
      • et al.
      Cerebral small-vessel disease and risk of incidence of depression: A meta-analysis of longitudinal cohort studies.
      ,
      • van Agtmaal M.J.M.
      • Houben A.J.H.M.
      • Pouwer F.
      • Stehouwer C.D.A.
      • Schram M.T.
      Association of microvascular dysfunction with late-life depression: A systematic review and meta-analysis.
      ) have consistently shown that cerebral small vessel disease features are associated with a higher risk of depression. Strongest associations were found for features located in regions involved in mood regulation, i.e., frontal and subcortical brain regions, compared with features in other brain regions (
      • Fang Y.
      • Qin T.
      • Liu W.
      • Ran L.
      • Yang Y.
      • Huang H.
      • et al.
      Cerebral small-vessel disease and risk of incidence of depression: A meta-analysis of longitudinal cohort studies.
      ,
      • van Sloten T.T.
      • Sigurdsson S.
      • van Buchem M.A.
      • Phillips C.L.
      • Jonsson P.V.
      • Ding J.
      • et al.
      Cerebral small vessel disease and association with higher incidence of depressive symptoms in a general elderly population: The AGES-Reykjavik Study.
      ). In contrast, results of neuropathology studies (
      • Tsopelas C.
      • Stewart R.
      • Savva G.M.
      • Brayne C.
      • Ince P.
      • Thomas A.
      • et al.
      Neuropathological correlates of late-life depression in older people.
      ,
      • Thomas A.J.
      • O’Brien J.T.
      • Davis S.
      • Ballard C.
      • Barber R.
      • Kalaria R.N.
      • Perry R.H.
      Ischemic basis for deep white matter hyperintensities in major depression: A neuropathological study.
      ,
      • Thomas A.J.
      • Ferrier I.N.
      • Kalaria R.N.
      • Perry R.H.
      • Brown A.
      • O’Brien J.T.
      A neuropathological study of vascular factors in late-life depression.
      ,
      • Santos M.
      • Gold G.
      • Kövari E.
      • Herrmann F.R.
      • Hof P.R.
      • Bouras C.
      • Giannakopoulos P.
      Neuropathological analysis of lacunes and microvascular lesions in late-onset depression.
      ,
      • Santos M.
      • Gold G.
      • Kövari E.
      • Herrmann F.R.
      • Bozikas V.P.
      • Bouras C.
      • Giannakopoulos P.
      Differential impact of lacunes and microvascular lesions on poststroke depression.
      ,
      • O’Brien J.
      • Thomas A.
      • Ballard C.
      • Brown A.
      • Ferrier N.
      • Jaros E.
      • Perry R.
      Cognitive impairment in depression is not associated with neuropathologic evidence of increased vascular or Alzheimer-type pathology.
      ,
      • Lloyd A.J.
      • Grace J.B.
      • Jaros E.
      • Perry R.H.
      • Fairbairn A.F.
      • Swann A.G.
      • et al.
      Depression in late life, cognitive decline and white matter pathology in two clinico-pathologically investigated cases.
      ) on the presence of cerebral small vessel disease in depression have been inconsistent. The results of these studies are, however, difficult to compare because of differences in patient populations, brain regions of interest, and the definitions used of cerebral small vessel disease features.

      Contribution of Microvascular Dysfunction to Apathy, Cognitive Dysfunction, and Stroke in Depression

      Depression, apathy, cognitive dysfunction, and stroke commonly occur together. Apathy, or diminished motivation, is a common symptom in late-life depression but may also exist independently of depression (
      • Ishii S.
      • Weintraub N.
      • Mervis J.R.
      Apathy: A common psychiatric syndrome in the elderly.
      ). In addition, late-life depression and apathy increase the risk of decline in any and multiple cognitive domains but most commonly in executive function and processing speed (
      • Alexopoulos G.S.
      Mechanisms and treatment of late-life depression.
      ). Furthermore, late-life depression and apathy are associated with a 1.5- to 2-fold higher risk of dementia (
      • Alexopoulos G.S.
      Mechanisms and treatment of late-life depression.
      ,
      • van Dalen J.W.
      • van Wanrooij L.L.
      • Moll van Charante E.P.
      • Brayne C.
      • van Gool W.A.
      • Richard E.
      Association of apathy with risk of incident dementia: A systematic review and meta-analysis.
      ) and stroke (
      • Pan A.
      • Sun Q.
      • Okereke O.I.
      • Rexrode K.M.
      • Hu F.B.
      Depression and risk of stroke morbidity and mortality: A meta-analysis and systematic review.
      ,
      • Dong J.Y.
      • Zhang Y.H.
      • Tong J.
      • Qin L.Q.
      Depression and risk of stroke: A meta-analysis of prospective studies.
      ).
      Increasing data suggest that the link between late-life depression, apathy, cognitive dysfunction, and stroke can be explained, at least in part, by microvascular dysfunction as a shared underlying mechanism. These disabilities may therefore be manifestations of a larger phenotype of global cerebral microvascular dysfunction. For example, the clustering of depression and executive dysfunction, also described as the depression-executive dysfunction syndrome (
      • Alexopoulos G.S.
      Mechanisms and treatment of late-life depression.
      ), has been related to higher white matter hyperintensity volume in the frontal and subcortical brain regions (
      • Gunning-Dixon F.M.
      • Walton M.
      • Cheng J.
      • Acuna J.
      • Klimstra S.
      • Zimmerman M.E.
      • et al.
      MRI signal hyperintensities and treatment remission of geriatric depression.
      ) and is associated with a lower response to current antidepressant medications (
      • Alexopoulos G.S.
      Mechanisms and treatment of late-life depression.
      ). Recent longitudinal data showed that only individuals with depressive symptoms that increased in late life and no other trajectories of depressive symptoms across the life course had higher white matter hyperintensity volumes (
      • Demnitz N.
      • Anatürk M.
      • Allan C.L.
      • Filippini N.
      • Griffanti L.
      • Mackay C.E.
      • et al.
      Association of trajectories of depressive symptoms with vascular risk, cognitive function and adverse brain outcomes: The Whitehall II MRI sub-study.
      ). In addition, only this trajectory has been associated with greater decline in executive function (
      • Demnitz N.
      • Anatürk M.
      • Allan C.L.
      • Filippini N.
      • Griffanti L.
      • Mackay C.E.
      • et al.
      Association of trajectories of depressive symptoms with vascular risk, cognitive function and adverse brain outcomes: The Whitehall II MRI sub-study.
      ) and higher risk of dementia (
      • Singh-Manoux A.
      • Dugravot A.
      • Fournier A.
      • Abell J.
      • Ebmeier K.
      • Kivimäki M.
      • Sabia S.
      Trajectories of depressive symptoms before diagnosis of dementia: A 28-year follow-up study.
      ,
      • Mirza S.S.
      • Wolters F.J.
      • Swanson S.A.
      • Koudstaal P.J.
      • Hofman A.
      • Tiemeier H.
      • Ikram M.A.
      10-year trajectories of depressive symptoms and risk of dementia: A population-based study.
      ). Also, various measures of microvascular dysfunction (e.g., retinal microvascular changes and blood biomarkers) have been associated with apathy (
      • Wouts L.
      • van Kessel M.
      • Beekman A.T.F.
      • Marijnissen R.M.
      • Oude Voshaar R.C.
      Empirical support for the vascular apathy hypothesis: A structured review.
      ) and cognitive dysfunction (
      • Rensma S.P.
      • van Sloten T.T.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral small vessel disease and risk of incident stroke, dementia and depression, and all-cause mortality: A systematic review and meta-analysis.
      ,
      • Smith P.J.
      • Blumenthal J.A.
      • Hinderliter A.L.
      • Watkins L.L.
      • Hoffman B.M.
      • Sherwood A.
      Microvascular endothelial function and neurocognition among adults with major depressive disorder.
      ,
      • Rensma S.P.
      • van Sloten T.T.
      • Houben A.J.H.M.
      • Köhler S.
      • van Boxtel M.P.J.
      • Berendschot T.T.J.M.
      • et al.
      Microvascular dysfunction is associated with worse cognitive performance: The Maastricht Study.
      ) in individuals without depression. In addition, presence and progression of cerebral small vessel disease over time, notably, increase in white matter hyperintensity volume and incident lacunar infarcts, have been associated with a higher risk of dementia (
      • Rensma S.P.
      • van Sloten T.T.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral small vessel disease and risk of incident stroke, dementia and depression, and all-cause mortality: A systematic review and meta-analysis.
      ,
      • Schmidt R.
      • Seiler S.
      • Loitfelder M.
      Longitudinal change of small-vessel disease-related brain abnormalities.
      ). Microvascular dysfunction has also been reported to be associated with an increased risk of stroke, notably lacunar ischemic stroke and deep hemorrhagic stroke (
      • Wardlaw J.M.
      • Smith C.
      • Dichgans M.
      Small vessel disease: Mechanisms and clinical implications.
      ), and with worse outcomes after stroke (
      IST-3 collaborative group
      Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third International Stroke Trial (IST-3): Secondary analysis of a randomised controlled trial.
      ,
      • Appleton J.P.
      • Woodhouse L.J.
      • Adami A.
      • Becker J.L.
      • Berge E.
      • Cala L.A.
      • et al.
      Imaging markers of small vessel disease and brain frailty, and outcomes in acute stroke.
      ).

      Drivers of Microvascular Dysfunction in Depression: Aging, Psychological Stress, Arterial Stiffness and Hypertension, and Type 2 Diabetes and the Metabolic Syndrome

      Aging

      Aging of the vasculature is an important contributor to cerebral microvascular dysfunction. Aging has been associated with increased blood-brain barrier permeability, lower cerebrovascular reactivity, altered cerebral autoregulation, and reduced cerebral microvascular perfusion (
      • Brown W.R.
      • Thore C.R.
      Review: Cerebral microvascular pathology in ageing and neurodegeneration.
      ). The factors involved in vascular aging are complex and include various cellular and molecular mechanisms, as reviewed previously (
      • Ungvari Z.
      • Tarantini S.
      • Sorond F.
      • Merkely B.
      • Csiszar A.
      Mechanisms of vascular aging, a geroscience perspective: JACC focus seminar.
      ).

      Psychological Stress and Inflammation

      Chronic stress is major risk factor for depression. For example, the association between objective stress-related environmental risk factors (e.g., neighborhood quality) and increased risk of depressive symptoms in adulthood is well established (
      • Ostir G.V.
      • Eschbach K.
      • Markides K.S.
      • Goodwin J.S.
      Neighbourhood composition and depressive symptoms among older Mexican Americans.
      ,
      • Kubzansky L.D.
      • Subramanian S.V.
      • Kawachi I.
      • Fay M.E.
      • Soobader M.J.
      • Berkman L.F.
      Neighborhood contextual influences on depressive symptoms in the elderly.
      ). Stress has multiple and complex effects on brain function and structure [as reviewed previously, e.g., (
      • Tracey K.J.
      Reflex control of immunity.
      ,
      • Lupien S.J.
      • McEwen B.S.
      • Gunnar M.R.
      • Heim C.
      Effects of stress throughout the lifespan on the brain, behaviour and cognition.
      )]. Emerging experimental data suggest that chronic stress also has detrimental effects on the microvasculature, mediated via inflammatory mechanisms, which may contribute to the development of depression (
      • Menard C.
      • Pfau M.L.
      • Hodes G.E.
      • Kana V.
      • Wang V.X.
      • Bouchard S.
      • et al.
      Social stress induces neurovascular pathology promoting depression.
      ,
      • Dudek K.A.
      • Dion-Albert L.
      • Lebel M.
      • LeClair K.
      • Labrecque S.
      • Tuck E.
      • et al.
      Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression.
      ,
      • Zhang Y.
      • Lu W.
      • Wang Z.
      • Zhang R.
      • Xie Y.
      • Guo S.
      • et al.
      Reduced neuronal cAMP in the nucleus accumbens damages blood-brain barrier integrity and promotes stress vulnerability.
      ). Chronic stress mobilizes the innate immune system and stimulates enhanced proliferation and release of inflammatory monocytes and neutrophils into the bloodstream (
      • Heidt T.
      • Sager H.B.
      • Courties G.
      • Dutta P.
      • Iwamoto Y.
      • Zaltsman A.
      • et al.
      Chronic variable stress activates hematopoietic stem cells.
      ). Animal studies have shown that this stress-induced inflammation can alter blood vessel morphology in the brain with discontinuous tight junctions, leading to greater blood-brain permeability (
      • Menard C.
      • Pfau M.L.
      • Hodes G.E.
      • Kana V.
      • Wang V.X.
      • Bouchard S.
      • et al.
      Social stress induces neurovascular pathology promoting depression.
      ,
      • Dudek K.A.
      • Dion-Albert L.
      • Lebel M.
      • LeClair K.
      • Labrecque S.
      • Tuck E.
      • et al.
      Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression.
      ,
      • Zhang Y.
      • Lu W.
      • Wang Z.
      • Zhang R.
      • Xie Y.
      • Guo S.
      • et al.
      Reduced neuronal cAMP in the nucleus accumbens damages blood-brain barrier integrity and promotes stress vulnerability.
      ). Greater blood-brain permeability was associated with depression-like behaviors in these models. For example, in a study of mice undergoing social defeat, a mouse model of chronic stress, it was shown that expression of the tight-junction protein claudin-5 in the blood-brain barrier was reduced in stress-susceptible animals (
      • Menard C.
      • Pfau M.L.
      • Hodes G.E.
      • Kana V.
      • Wang V.X.
      • Bouchard S.
      • et al.
      Social stress induces neurovascular pathology promoting depression.
      ). This promoted the passage of interleukin 6 across the blood-brain barrier and induced depressive-like behaviors in these animals. Furthermore, other studies showed that anti-inflammatory therapy was able to reduce stress-induced increases in blood-brain barrier permeability and lower depressive symptoms (
      • Cheng Y.
      • Desse S.
      • Martinez A.
      • Worthen R.J.
      • Jope R.S.
      • Beurel E.
      TNFα disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice.
      ). Whether these findings can be translated to humans remains to be investigated.

      Arterial Stiffness, Hypertension, and Blood Pressure Fluctuations

      Large artery stiffness and hypertension may lead to cerebral microvascular dysfunction (
      • Climie R.E.
      • van Sloten T.T.
      • Bruno R.M.
      • Taddei S.
      • Empana J.P.
      • Stehouwer C.D.A.
      • et al.
      Macrovasculature and microvasculature at the crossroads between type 2 diabetes mellitus and hypertension.
      ). Stiffening of large arteries impairs their cushioning function and increases blood pressure and flow pulsatility (Figure 3). This increased pulsatile load may transmit distally into the cerebral circulation and thereby contribute to cerebral microvascular damage (
      • Climie R.E.
      • van Sloten T.T.
      • Bruno R.M.
      • Taddei S.
      • Empana J.P.
      • Stehouwer C.D.A.
      • et al.
      Macrovasculature and microvasculature at the crossroads between type 2 diabetes mellitus and hypertension.
      ). The microvasculature of the brain is particularly vulnerable because it is characterized by high flow and low impedance, allowing the pulsatile load to penetrate deeply into its microvascular bed (
      • Mitchell G.F.
      Effects of central arterial aging on the structure and function of the peripheral vasculature: Implications for end-organ damage.
      ). Consistently, recent population-based data (
      • van Sloten T.T.
      • Boutouyrie P.
      • Tafflet M.
      • Offredo L.
      • Thomas F.
      • Guibout C.
      • et al.
      Carotid artery stiffness and incident depressive symptoms: The Paris Prospective Study III.
      ) showed that greater stiffness of the carotid artery is associated with a higher risk of depressive symptoms. In addition, cross-sectional data from another large study (
      • van Sloten T.T.
      • Mitchell G.F.
      • Sigurdsson S.
      • van Buchem M.A.
      • Jonsson P.V.
      • Garcia M.E.
      • et al.
      Associations between arterial stiffness, depressive symptoms and cerebral small vessel disease: Cross-sectional findings from the AGES-Reykjavik Study.
      ) showed that the association between greater arterial stiffness and presence of depressive symptoms was in part explained, or mediated, by features of cerebral small vessel disease. In addition, some studies (
      • Armstrong N.M.
      • Meoni L.A.
      • Carlson M.C.
      • Xue Q.L.
      • Bandeen-Roche K.
      • Gallo J.J.
      • Gross A.L.
      Cardiovascular risk factors and risk of incident depression throughout adulthood among men: The Johns Hopkins Precursors Study.
      ,
      • Zimmerman J.A.
      • Mast B.T.
      • Miles T.
      • Markides K.S.
      Vascular risk and depression in the Hispanic Established Population for the Epidemiologic Study of the Elderly (EPESE).
      ), but not all (
      • Luijendijk H.J.
      • Stricker B.H.
      • Hofman A.
      • Witteman J.C.
      • Tiemeier H.
      Cerebrovascular risk factors and incident depression in community-dwelling elderly.
      ,
      • Mast B.T.
      • Miles T.
      • Penninx B.W.
      • Yaffe K.
      • Rosano C.
      • Satterfield S.
      • et al.
      Vascular disease and future risk of depressive symptomatology in older adults: Findings from the Health, Aging, and Body Composition study.
      ), have shown that hypertension is associated with a higher risk of depression in older individuals.
      Figure thumbnail gr3
      Figure 3Presumed pathway by which arterial stiffness contributes to cerebral microvascular dysfunction and late-onset depression. Stiffening of large arteries impairs their cushioning function and increases pressure and flow pulsatility. This increased load may cause direct microvascular damage and may induce a microvascular remodeling response (
      • Climie R.E.
      • van Sloten T.T.
      • Bruno R.M.
      • Taddei S.
      • Empana J.P.
      • Stehouwer C.D.A.
      • et al.
      Macrovasculature and microvasculature at the crossroads between type 2 diabetes mellitus and hypertension.
      ). This response initially serves to limit the penetration of the pulsatile load into the microvascular system by raising cerebrovascular resistance (
      • Mitchell G.F.
      • van Buchem M.A.
      • Sigurdsson S.
      • Gotal J.D.
      • Jonsdottir M.K.
      • Kjartansson Ó.
      • et al.
      Arterial stiffness, pressure and flow pulsatility and brain structure and function: The Age, Gene/Environment Susceptibility--Reykjavik study.
      ). However, this protective response may ultimately become unfavorable, leading to impaired vasoreactivity and hypoperfusion. In addition, arterial stiffening may cause excessive blood pressure fluctuations that may further sensitize organs to the harmful effects of impaired microvascular vasoreactivity (
      • Climie R.E.
      • van Sloten T.T.
      • Bruno R.M.
      • Taddei S.
      • Empana J.P.
      • Stehouwer C.D.A.
      • et al.
      Macrovasculature and microvasculature at the crossroads between type 2 diabetes mellitus and hypertension.
      ).
      Arterial stiffening may also contribute to substantial fluctuations in blood pressure, including orthostatic hypotension and exercise-induced hypertension (
      • Climie R.E.
      • van Sloten T.T.
      • Bruno R.M.
      • Taddei S.
      • Empana J.P.
      • Stehouwer C.D.A.
      • et al.
      Macrovasculature and microvasculature at the crossroads between type 2 diabetes mellitus and hypertension.
      ). Greater blood pressure fluctuations may further sensitize the brain to the harmful effects of impaired microvascular-related cerebral autoregulation and vasoreactivity, with cerebral hypoperfusion during hypotension and overexposure to high pulsatility at high pressure (Figure 3). In accordance, studies have shown that orthostatic hypotension (
      • Briggs R.
      • Carey D.
      • Kennelly S.P.
      • Kenny R.A.
      Longitudinal association between orthostatic hypotension at 30 seconds post-standing and late-life depression.
      ) and exercise-induced hypertension (
      • Zhou T.L.
      • Kroon A.A.
      • Henry R.M.A.
      • Koster A.
      • Dagnelie P.C.
      • Bosma H.
      • et al.
      Exercise SBP response and incident depressive symptoms: The Maastricht Study.
      ) are associated with higher risk of depressive symptoms.

      Type 2 Diabetes and Metabolic Syndrome

      Type 2 diabetes and late-life depression commonly co-occur; individuals with type 2 diabetes have a doubled risk for depression as compared with individuals without type 2 diabetes. Furthermore, individuals with depression have a 1.5 times higher risk of type 2 diabetes (
      • van Sloten T.
      • Schram M.
      Understanding depression in type 2 diabetes: A biological approach in observational studies.
      ). The mechanisms underlying the relationship between type 2 diabetes and late-life depression are likely multifactorial and may include psychosocial factors, e.g., diabetes burden and distress, and biological factors, including central insulin resistance (
      • Lyra E Silva N.M.
      • Lam M.P.
      • Soares C.N.
      • Munoz D.P.
      • Milev R.
      • De Felice F.G.
      Insulin resistance as a shared pathogenic mechanism between depression and type 2 diabetes.
      ) and microvascular dysfunction (
      • van Sloten T.T.
      • Sedaghat S.
      • Carnethon M.R.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral microvascular complications of type 2 diabetes: Stroke, cognitive dysfunction, and depression.
      ).
      Microvascular dysfunction is present in many organs in individuals with diabetes or the metabolic syndrome, including the brain (
      • van Sloten T.T.
      • Sedaghat S.
      • Carnethon M.R.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral microvascular complications of type 2 diabetes: Stroke, cognitive dysfunction, and depression.
      ). Some evidence also suggests that depression in diabetes may be associated with microvascular dysfunction. One cross-sectional study found that individuals with type 2 diabetes and depression had wider retinal arterioles than individuals with type 2 diabetes but without depression (
      • Nguyen T.T.
      • Wong T.Y.
      • Islam F.M.
      • Hubbard L.
      • Ajilore O.
      • Haroon E.
      • et al.
      Evidence of early retinal microvascular changes in patients with type 2 diabetes and depression.
      ), consistent with an association between depression and early microvascular changes in diabetes. Moreover, a recent, population-based large study found that individuals with type 2 diabetes had greater increase in depressive symptoms over time, and cerebral small vessel disease partly explained this association (
      • Rensma S.P.
      • van Sloten T.T.
      • Ding J.
      • Sigurdsson S.
      • Stehouwer C.D.A.
      • Gudnason V.
      • Launer L.J.
      Type 2 diabetes, change in depressive symptoms over time, and cerebral small vessel disease: Longitudinal data of the AGES-Reykjavik Study.
      ). Type 2 diabetes and the metabolic syndrome are also associated with accelerated stiffening of large arteries (
      • Climie R.E.
      • van Sloten T.T.
      • Bruno R.M.
      • Taddei S.
      • Empana J.P.
      • Stehouwer C.D.A.
      • et al.
      Macrovasculature and microvasculature at the crossroads between type 2 diabetes mellitus and hypertension.
      ), and this may contribute to depression in these individuals (
      • Dregan A.
      • Rayner L.
      • Davis K.A.S.
      • Bakolis I.
      • Arias de la Torre J.
      • Das-Munshi J.
      • et al.
      Associations between depression, arterial stiffness, and metabolic syndrome among adults in the UK Biobank Population Study: A mediation analysis.
      ). Importantly, cerebral microvascular blood flow may be increased in early type 2 diabetes, possibly to compensate for reduced oxygen extraction efficacy related to subtle, or early, microvascular dysfunction, whereas in more advanced stages of the disease, blood flow may be reduced (
      • van Sloten T.T.
      • Sedaghat S.
      • Carnethon M.R.
      • Launer L.J.
      • Stehouwer C.D.A.
      Cerebral microvascular complications of type 2 diabetes: Stroke, cognitive dysfunction, and depression.
      ). Because of this high flow state in early diabetes, the increased pulsatile load associated with arterial stiffening may penetrate more deeply into the cerebral microvascular bed and contribute to cerebral damage (
      • Climie R.E.
      • van Sloten T.T.
      • Bruno R.M.
      • Taddei S.
      • Empana J.P.
      • Stehouwer C.D.A.
      • et al.
      Macrovasculature and microvasculature at the crossroads between type 2 diabetes mellitus and hypertension.
      ). This suggests that individuals with type 2 diabetes may be more vulnerable for the detrimental effects of arterial stiffening on the brain, but this requires further study.

      Potential Therapeutic Targets and Interventions

      Vascular-related depression is associated with poor response to current antidepressant treatments (
      • Taylor W.D.
      • Schultz S.K.
      • Panaite V.
      • Steffens D.C.
      Perspectives on the management of vascular depression.
      ). In addition, there are no current evidence-based primary prevention pharmacotherapies for late-onset depression. The identification of cerebral microvascular dysfunction as a potential contributor to depression could allow for the development of more effective prevention and treatment strategies. In this context, targeting cerebral microvascular function as a complementary treatment strategy of late-onset depression would represent a paradigm shift in the management of late-onset depression.
      Currently, no therapeutic agents are available that specifically enhance microvascular function in the brain. Yet, some established therapies that are approved for diseases other than depression have been linked to improved cerebral microvascular function and might also be beneficial in depression as discussed below. It has been hypothesized that some currently used antidepressant medications targeting neurotransmitters may also have vasoprotective effects. However, data in humans are scarce, and results have been inconsistent (
      • Kahl K.G.
      • Westhoff-Bleck M.
      • Krüger T.H.C.
      Effects of psychopharmacological treatment with antidepressants on the vascular system.
      ).

      Lifestyle Factors

      Microvascular dysfunction might be at least partly reversible through weight loss and exercise (
      • Stehouwer C.D.A.
      Microvascular dysfunction and hyperglycemia: A vicious cycle with widespread consequences.
      ). Recent meta-analyses suggest that exercise and weight loss interventions have a beneficial effect on depressive symptoms across a wide age range, including older individuals (
      • Hu M.X.
      • Turner D.
      • Generaal E.
      • Bos D.
      • Ikram M.K.
      • Ikram M.A.
      • et al.
      Exercise interventions for the prevention of depression: A systematic review of meta-analyses.
      ,
      • Jones R.A.
      • Lawlor E.R.
      • Birch J.M.
      • Patel M.I.
      • Werneck A.O.
      • Hoare E.
      • et al.
      The impact of adult behavioural weight management interventions on mental health: A systematic review and meta-analysis.
      ). To what extent any effects of these interventions are mediated by improvement of microvascular function remains to be elucidated.

      Pharmacological Interventions

      Various drugs may improve microvascular function, including renin-angiotensin system (RAS) inhibitors, calcium antagonists, glucose-lowering drugs, statins, anti-inflammatory therapies, and drugs that enhance signaling of nitric oxide or prostacyclin.
      RAS inhibitors, i.e., angiotensin converting enzyme inhibitors and angiotensin receptor 2 blockers, are commonly prescribed antihypertensive drugs. Experimental studies suggest that these drugs may improve the function of small vessels beyond their blood-lowering effects via upregulation of endothelial nitric oxide synthetase (
      • Trauernicht A.K.
      • Sun H.
      • Patel K.P.
      • Mayhan W.G.
      Enalapril prevents impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in diabetic rats.
      ,
      • Yamakawa H.
      • Jezova M.
      • Ando H.
      • Saavedra J.M.
      Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition.
      ,
      • Ando H.
      • Zhou J.
      • Macova M.
      • Imboden H.
      • Saavedra J.M.
      Angiotensin II AT1 receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats.
      ) and via their anti-inflammatory effects (
      • Luo H.
      • Wu P.F.
      • Cao Y.
      • Jin M.
      • Shen T.T.
      • Wang J.
      • et al.
      Angiotensin-converting enzyme inhibitor rapidly ameliorates depressive-type behaviors via bradykinin-dependent activation of mammalian target of rapamycin complex 1.
      ). There are no randomized clinical trials of RAS inhibitors and depression. However, experimental data suggest that RAS inhibitors may have mood-elevating effects (
      • Luo H.
      • Wu P.F.
      • Cao Y.
      • Jin M.
      • Shen T.T.
      • Wang J.
      • et al.
      Angiotensin-converting enzyme inhibitor rapidly ameliorates depressive-type behaviors via bradykinin-dependent activation of mammalian target of rapamycin complex 1.
      ). Moreover, some (
      • Kessing L.V.
      • Rytgaard H.C.
      • Ekstrøm C.T.
      • Torp-Pedersen C.
      • Berk M.
      • Gerds T.A.
      Antihypertensive drugs and risk of depression: A nationwide population-based study.