The Enigma of Vascular Depression

Editorial

Austin Alzheimers J Parkinsons Dis. 2016; 3(1): 1026.

The Enigma of Vascular Depression

Jellinger KA*

Institute of Clinical Neurobiology, Vienna, Austria

*Corresponding author: Jellinger KA, Institute of Clinical Neurobiology, Alberichgasse 5/13, A-1150 Vienna, Austria

Received: April 22, 2016; Accepted: April 27, 2016; Published: April 28, 2016

Editorial

Vascular Depression (VaDep) is regarded as a subtype of Late-Life Depression (LLD) characterized by a distinct clinical presentation associated with cerebrovascular damage. Although depressive symptoms in the elderly (around/after 60 years) are common (estimated at 12-50% of Major Depressive Disorder/MDD), the concept of VaDep is still not widely accepted, validated diagnostic criteria are lacking, and it is not included in current psychiatric manuals as DSM-V, a fact that limits its use in clinical settings. After the International Congress on Vascular Dementia 2015 in Ljubljana, an international group of experts has prepared a Consensus Report on the clinical features, brain lesions detected by MRI and neuropathology (microvascular burden, gray and white matter lesions, and other structural brain changes), clinico-pathological correlations, and the current evidence for the neuropathobiology of VaDep [1].

The “VaDep hypothesis”, introduced by Alexopoulos et al. in 1997 [2], suggested that cerebrovascular disease, in particular subcortical microvascular and white matter lesions, may predispose, precipitate or perpetuate depressive symptoms in aged people as a consequence of structural damage to fronto-subcortical circuits. Later, the term “MRI-defined VaDep” was introduced [3], supporting the hypothesis that loss of brain volume and white matter integrity are associated with depressive symptoms in the aged [4], although this has not been confirmed by others [5,6].

The clinical manifestations of VaDep, characterized by psychomotor slowing, lack of initiative, apathy, executive dysfunction, impaired processing speed, more motivational problems, risk of cognitive impairment, and poorer outcome, summarized as “depressive-executive syndrome” [7], are distinct from non-vascular depression in the elderly without risk of suicidal activity, agitation and a family history of depression [8,9].

Individuals with LLD in general are at greater risk to develop cognitive impairment, more likely related to Vascular Dementia (VaD) than to Alzheimer Disease (AD) [10]. However, recent data showed that LLD and VaDep are not a risk factor for AD [6,11], although older cognitively unimpaired patients with depressive episodes may have more underlying AD pathology, in particular β-amyloid deposition [12], leading to the amyloid hypothesis of LLD [13]. In general, depression in VaD is clinically different from that in AD [10].

MRI-defined VaDep requires neuroimaging evidence of cerebrovascular changes, in particular White Matter Hypointensities (WMH) and subcortical microinfarcts (lacunes), which may predate the development of depressive symptoms, WMH volume showing a strong relationship with depression [14]. While others could not demonstrate such an association [15], large confluent WMHs are associated with persistent depressive symptoms, poorer executive function and cognitive impairment [16,17]. Additional gray matter changes in orbitofrontal cortex, hippocampus, amygdala and other subcortical areas, causing disruption of fronto-limbic and corticostriatal networks, are associated with both depressive symptoms and cognitive decline [18]. WMHs especially within cortico-subcortical neuronal circuits may be interpreted as sequelae of underlying microstructural dysfunctions affecting major brain connectivities, suggesting an association between cerebrovascular disease and depression [19, 20]. However, not all studies supported the relevance of WMHs for VaDep [21,22]. Post-mortem studies in clinically welldocumented cases of LLD did not confirm the notion that diffuse WMHs, subcortical microvascular lesions, cortical microinfarcts or AD pathology including Cerebral Amyloid Angiopathy (CAA) may be essential for the development of LLD [6,23-28], challenging the “VaDep hypothesis” and revealing a significant gap in our understanding of the pathobiology of LLD. It should be admitted that other, nonvascular factors, like aging, neuroinflammation, glial and amyloid pathology or affection of the mesolimbic dopamine system may also contribute to VaDep [29-31].

Although there is considerable empiric support for the validity of a VaDep subtype of LLD, fundamental questions remain open, including how the illness is defined, how vascular disease and depression influence each other, why VaDep is not a progressive disorder although the possibly related brain lesions tend to accumulate, and whether WMHs and global vascular risk factors are responsible for poor outcome and poor response to antidepressive treatment [13,32,33]. Genetic, neuroinflammatory, cardio- and cerebrovascular, neurodegenerative and other hitherto unknown factors may all be involved in the complex pathogenetic cascade that precedes depressive, behavioral and cognitive symptoms in advanced age. A growing body of evidence from neuroimaging and peripheral biomarker studies suggests that depressive symptoms in old age may be associated with vascular-related and other pathobiological processes, but the theory of VaDep as a distinct subtype of LLD is still not fully established. There are several possible interrelations between cerebrovascular disease and depressive symptoms: (1) Depression as the consequence of vascular disease; (2) development of depression independent of vascular disease, which, however, may stimulate the onset and course of depression; (3) cerebrovascular disease and depression are two manifestations of similar pathogenetic mechanisms. Since the temporal relationship between brain pathology and depressive and related symptoms as well as the etiology of VaDep cannot be established on the basis of post-mortem findings alone, long-term clinico-pathologic studies including premortem and postmortem neuroimaging are needed in order to further elucidate the relations between structural/functional brain lesions, related molecular-biology and depression in advanced age in order to definitely establish the existence of VaDep as a subtype of LLD as a basis for the prevention and successful treatment of this disorder.

References

  1. Aizenstein H, Baskys A, Boldrini M, Butters MA, Diniz BS, Jaiswal MK, et al. Vascular depression consensus report. BMC Med. 2016.
  2. Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M. 'Vascular depression' hypothesis. Arch Gen Psychiatry. 1997; 54: 915-922.
  3. Krishnan KR, Hays JC, Blazer DG. MRI-defined vascular depression. Am J Psychiatry. 1997; 154: 497-501.
  4. Pimontel MA, Reinlieb ME, Johnert LC, Garcon E, Sneed JR, Roose SP. The external validity of MRI-defined vascular depression. Int J Geriatr Psychiatry. 2013; 28: 1189-1196.
  5. Thuile J, Even C, Guelfi JD. [Validity of vascular depression as a specific diagnostic: a review]. Encephale. 2007; 33: 39-48.
  6. Jellinger KA. Organic bases of late-life depression: a critical update. J Neural Transm (Vienna). 2013; 120: 1109-1125.
  7. Taylor WD, Aizenstein HJ, Alexopoulos GS. The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol Psychiatry. 2013; 18: 963-974.
  8. Krishnan KR, Taylor WD, McQuoid DR, MacFall JR, Payne ME, Provenzale JM, et al. Clinical characteristics of magnetic resonance imaging-defined subcortical ischemic depression. Biol Psychiatry. 2004; 55: 390-397.
  9. Zuidersma M, Izaks GJ, Naarding P, Comijs HC, Oude Voshaar RC. Vascular burden and cognitive function in late-life depression. Am J Geriatr Psychiatry. 2015; 23: 514-524.
  10. Diniz BS, Butters MA, Albert SM, Dew MA, Reynolds CF 3rd. Late-life depression and risk of vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies. Br J Psychiatry. 2013; 202: 329-335.
  11. Naismith SL, Norrie LM, Mowszowski L, Hickie IB. The neurobiology of depression in later-life: clinical, neuropsychological, neuroimaging and pathophysiological features. Prog Neurobiol. 2012; 98: 99-143.
  12. Yasuno F, Kazui H, Morita N, Kajimoto K, Ihara M, Taguchi A. High amyloid-î² deposition related to depressive symptoms in older individuals with normal cognition: a pilot study. Int J Geriatr Psychiatry. 2016.
  13. Mahgoub N, Alexopoulos GS. Amyloid Hypothesis: Is There a Role for Antiamyloid Treatment in Late-Life Depression? Am J Geriatr Psychiatry. 2016; 24: 239-247.
  14. Godin O, Dufouil C, Maillard P, Delcroix N, Mazoyer B, Crivello F, et al. White matter lesions as a predictor of depression in the elderly: the 3C-Dijon study. Biol Psychiatry. 2008; 63: 663-669.
  15. Firbank MJ, Teodorczuk A, van der Flier WM, Gouw AA, Wallin A, Erkinjuntti T, et al. Relationship between progression of brain white matter changes and late-life depression: 3-year results from the LADIS study. Br J Psychiatry. 2012; 201: 40-45.
  16. Grool AM, van der Graaf Y, Mali WP, Geerlings MI. Location of cerebrovascular and degenerative changes, depressive symptoms and cognitive functioning in later life: the SMART-Medea study. J Neurol Neurosurg Psychiatry. 2011; 82: 1093-1100.
  17. Prins ND, Scheltens P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol. 2015; 11: 157-165.
  18. Gudmundsson P, Olesen PJ, Simoni M, Pantoni L, Östling S, Kern S, et al. White matter lesions and temporal lobe atrophy related to incidence of both dementia and major depression in 70-year-olds followed over 10 years. Eur J Neurol. 2015; 22: 781-788, e49-50.
  19. Serafini G, Amore M, Rihmer Z. Microstructural brain abnormalities, affective temperaments, and suicidal behavior in patients with major depression. Neuroimmunol Neuroinflammation. 2015; 2: 200-214.
  20. Brookes RL, Herbert V, Lawrence AJ, Morris RG, Markus HS. Depression in small-vessel disease relates to white matter ultrastructural damage, not disability. Neurology. 2014; 83: 1417-1423.
  21. Choi KS, Holtzheimer PE, Franco AR, Kelley ME, Dunlop BW, Hu XP, et al. Reconciling variable findings of white matter integrity in major depressive disorder. Neuropsychopharmacology. 2014; 39: 1332-1339.
  22. Bezerra DM, Pereira FR, Cendes F, Jackowski MP, Nakano EY, Moscoso MA, et al. DTI voxelwise analysis did not differentiate older depressed patients from older subjects without depression. J Psychiatr Res. 2012; 46: 1643-1649.
  23. Santos M, Kövari E, Hof PR, Gold G, Bouras C, Giannakopoulos P. The impact of vascular burden on late-life depression. Brain Res Rev. 2009; 62: 19-32.
  24. Xekardaki A, Santos M, Hof P, Kövari E, Bouras C, Giannakopoulos P. Neuropathological substrates and structural changes in late-life depression: the impact of vascular burden. Acta Neuropathol. 2012; 124: 453-464.
  25. Santos M, Gold G, Kövari E, Herrmann FR, Hof PR, Bouras C, et al. Neuropathological analysis of lacunes and microvascular lesions in late-onset depression. Neuropathol Appl Neurobiol. 2010; 36: 661-672.
  26. Tsopelas C, Stewart R, Savva GM, Brayne C, Ince P, Thomas A, et al. Medical Research Council Cognitive Function and Ageing Study. Neuropathological correlates of late-life depression in older people. Br J Psychiatry. 2011; 198: 109-114.
  27. Wilson RS, Schneider JA, Bienias JL, Arnold SE, Evans DA, Bennett DA. Depressive symptoms, clinical AD, and cortical plaques and tangles in older persons. Neurology. 2003; 61: 1102-1107.
  28. Beekman AT. Neuropathological correlates of late-life depression. Expert Rev Neurother. 2011; 11: 947-949.
  29. Paradise MB, Naismith SL, Norrie LM, Graeber MB, Hickie IB. The role of glia in late-life depression. Int Psychogeriatr. 2012; 24: 1878-1890.
  30. Torres-Platas SG, Nagy C, Wakid M, Turecki G, Mechawar N. Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides. Mol Psychiatry. 2016; 21: 509-515.
  31. Medina A, Watson SJ, Bunney W Jr, Myers RM, Schatzberg A, Barchas J, et al. Evidence for alterations of the glial syncytial function in major depressive disorder. J Psychiatr Res. 2016; 72: 15-21.
  32. Brunoni AR, Benseñor IM, Alves TC. Therapeutic interventions for vascular depression: a systematic review. Rev Bras Psiquiatr. 2011; 33: 400-409.
  33. Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H, et al. Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology. 2013; 38: 1068-1077.

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Citation: Jellinger KA. The Enigma of Vascular Depression. Austin Alzheimers J Parkinsons Dis. 2016; 3(1): 1026. ISSN: 2377-357X

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