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Localization of white-matter lesions and effect of vascular risk factors in late-onset major depression

  • R. B. Dalby (a1), M. M. Chakravarty (a2) (a3) (a4), J. Ahdidan (a1), L. Sørensen (a5), J. Frandsen (a4), K. Y. Jonsdottir (a4), E. Tehrani (a1), R. Rosenberg (a1), L. Østergaard (a4) and P. Videbech (a1)...



Several studies suggest that patients with late-onset major depression (MD) have an increased load of cerebral white-matter lesions (WMLs) compared with age-matched controls. Vascular risk factors such as hypertension and smoking may confound such findings. Our aim was to investigate the association between the localization and load of WMLs in late-onset MD with respect to vascular risk factors.


We examined 22 consecutive patients with late-onset first-episode MD and 22 age- and gender-matched controls using whole-brain magnetic resonance imaging (MRI). The localization, number and volume of WMLs were compared between patients and controls, while testing the effect of vascular risk factors.


Among subjects with one or more WMLs, patients displayed a significantly higher WML density in two white-matter tracts: the left superior longitudinal fasciculus and the right frontal projections of the corpus callosum. These tracts are part of circuitries essential for cognitive and emotional functions. Analyses revealed no significant difference in the total number and volume of WMLs between groups. Patients and controls showed no difference in vascular risk factors, except for smoking. Lesion load was highly correlated with smoking.


Our results indicate that lesion localization rather than lesion load differs between patients with late-onset MD and controls. Increased lesion density in regions associated with cognitive and emotional functions may be crucial in late-onset MD, and vascular risk factors such as smoking may play an important role in the pathophysiology of late-onset MD, consistent with the vascular depression hypothesis.


Corresponding author

*Address for correspondence: Dr R. B. Dalby, Center for Psychiatric Research, Aarhus University Hospital, Skovagervej 2, DK-8240 Risskov, Denmark. (Email:


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Alexopoulos, GS, Meyers, BS, Young, RC, Campbell, S, Silbersweig, D, Charlson, M (1997 a). ‘Vascular depression’ hypothesis. Archives of General Psychiatry 54, 915922.
Alexopoulos, GS, Meyers, BS, Young, RC, Kakuma, T, Silbersweig, D, Charlson, M (1997 b). Clinically defined vascular depression. American Journal of Psychiatry 154, 562565.
APA (2000). Diagnostic and Statistical Manual of Mental Disorders, 4th edn, text revision. American Psychiatric Association: Washington, DC.
Austin, MP, Mitchell, P, Goodwin, GM (2001). Cognitive deficits in depression: possible implications for functional neuropathology. British Journal of Psychiatry 178, 200206.
Awad, IA, Spetzler, RF, Hodak, JA, Awad, CA, Carey, R (1986). Incidental subcortical lesions identified on magnetic resonance imaging in the elderly. I. Correlation with age and cerebrovascular risk factors. Stroke 17, 10841089.
Bech, P (2002). The Bech–Rafaelsen Melancholia Scale (MES) in clinical trials of therapies in depressive disorders: a 20-year review of its use as outcome measure. Acta Psychiatrica Scandinavica 106, 252264.
Breteler, MMB, van Swieten, JC, Bots, ML, Grobbee, DE, Claus, JJ, van den Hout, JHW, van Harskamp, F, Tanghe, HLJ, de Jong, PTVM, van Gijn, J, Hofman, A (1994). Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: the Rotterdam Study. Neurology 44, 12461252.
Brodmann, K, Gary, LJ (2006). Brodmann's Localisation in the Cerebral Cortex: The Principles of Comparative Localisation in the Cerebral Cortex based on Cytoarchitectonics. Springer: New York, NY.
Cao, J (1999). The size of the connected components of excursion sets of x2, T and F fields. Advances in Applied Probability 31, 579595.
Chen, PS, McQuoid, DR, Payne, ME, Steffens, DC (2006). White matter and subcortical gray matter lesion volume changes and late-life depression outcome: a 4-year magnetic resonance imaging study. International Psychogeriatrics 18, 445456.
Chouinard, PA, Paus, T (2006). The primary motor and premotor areas of the human cerebral cortex. Neuroscientist 12, 143152.
Collins, DL, Holmes, CJ, Peters, TM, Evans, AC (1995). Automatic 3-D model-based neuroanatomical segmentation. Human Brain Mapping 3, 190208.
Collins, DL, Neelin, P, Peters, TM, Evans, AC (1994). Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. Journal of Computer Assisted Tomography 18, 192205.
de Leeuw, FE, de Groot, JC, Achten, E, Oudkerk, M, Ramos, LM, Heijboer, R, Hofman, A, Jolles, J, van Gijn, J, Breteler, MM (2001). Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. Journal of Neurology, Neurosurgery and Psychiatry 70, 9–14.
Drevets, WC (2007). Orbitofrontal cortex function and structure in depression. Annals of the New York Academy of Sciences 1121, 499527.
Evans, AC, Collins, DL, Mills, SR, Brown, ED, Kelly, RL, Peters, TM (1994). 3D statistical neuroanatomical models from 305 MRI volumes. In Proceedings of the 1993 IEEE Nuclear Science Symposium & Medical Imaging Conference. San Francisco, CA, USA: IEEE, pp. 18131817.
Fazekas, F, Barkhof, F, Wahlund, LO, Pantoni, L, Erkinjuntti, T, Scheltens, P, Schmidt, R (2002). CT and MRI rating of white matter lesions. Cerebrovascular Diseases 13 (Suppl. 2), 3136.
Fazekas, F, Kleinert, R, Offenbacher, H, Schmidt, R, Kleinert, G, Payer, F, Radner, H, Lechner, H (1993). Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 43, 16831689.
Folstein, MF, Folstein, SE, McHugh, PR (1975). ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12, 189198.
Goodwin, GM (1997). Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression. Journal of Psychopharmacology 11, 115122.
Greenwald, BS, Kramer-Ginsberg, E, Krishnan, KR, Ashtari, M, Auerbach, C, Patel, M (1998). Neuroanatomic localization of magnetic resonance imaging signal hyperintensities in geriatric depression. Stroke 29, 613617.
Gunning-Dixon, FM, Raz, N (2000). The cognitive correlates of white matter abnormalities in normal aging: a quantitative review. Neuropsychology 14, 224232.
Haggard, P (2008). Human volition: towards a neuroscience of will. Nature Reviews Neuroscience 9, 934946.
Herrmann, LL, Goodwin, GM, Ebmeier, KP (2007). The cognitive neuropsychology of depression in the elderly. Psychological Medicine 37, 16931702.
Herrmann, LL, Le Masurier, M, Ebmeier, KP (2008). White matter hyperintensities in late life depression: a systematic review. Journal of Neurology, Neurosurgery and Psychiatry 79, 619624.
Hickie, I, Scott, E, Mitchell, P, Wilhelm, K, Austin, MP, Bennett, B (1995). Subcortical hyperintensities on magnetic resonance imaging: clinical correlates and prognostic significance in patients with severe depression. Biological Psychiatry 37, 151160.
Hudson, CG (2005). Socioeconomic status and mental illness: tests of the social causation and selection hypotheses. American Journal of Orthopsychiatry 75, 3–18.
Iosifescu, DV, Renshaw, PF, Lyoo, IK, Lee, HK, Perlis, RH, Papakostas, GI, Nierenberg, AA, Fava, M (2006). Brain white-matter hyperintensities and treatment outcome in major depressive disorder. British Journal of Psychiatry 188, 180185.
Jane-Llopis, E, Matytsina, I (2006). Mental health and alcohol, drugs and tobacco: a review of the comorbidity between mental disorders and the use of alcohol, tobacco and illicit drugs. Drug and Alcohol Review 25, 515536.
Kales, HC, Maixner, DF, Mellow, AM (2005). Cerebrovascular disease and late-life depression. American Journal of Geriatric Psychiatry 13, 8898.
Kendler, KS, Neale, MC, MacLean, CJ, Heath, AC, Eaves, LJ, Kessler, RC (1993). Smoking and major depression. A causal analysis. Archives of General Psychiatry 50, 3643.
Krawczyk, DC (2002). Contributions of the prefrontal cortex to the neural basis of human decision making. Neuroscience and Biobehavioral Reviews 26, 631664.
Krishnan, KR, Hays, JC, Blazer, DG (1997). MRI-defined vascular depression. American Journal of Psychiatry 154, 497501.
Krishnan, KR, McDonald, WM (1995). Arteriosclerotic depression. Medical Hypotheses 44, 111115.
Krishnan, KR, Taylor, WD, McQuoid, DR, MacFall, JR, Payne, ME, Provenzale, JM, Steffens, DC (2004). Clinical characteristics of magnetic resonance imaging-defined subcortical ischemic depression. Biological Psychiatry 55, 390397.
Krishnan, MS, O'Brien, JT, Firbank, MJ, Pantoni, L, Carlucci, G, Erkinjuntti, T, Wallin, A, Wahlund, LO, Scheltens, P, van Straaten, EC, Inzitari, D (2006). Relationship between periventricular and deep white matter lesions and depressive symptoms in older people. The LADIS Study. International Journal of Geriatric Psychiatry 21, 983989.
Liao, D, Cooper, L, Cai, J, Toole, J, Bryan, N, Burke, G, Shahar, E, Nieto, J, Mosley, T, Heiss, G (1997). The prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: the ARIC Study. Neuroepidemiology 16, 149162.
MacFall, JR, Payne, ME, Provenzale, JE, Krishnan, KR (2001). Medial orbital frontal lesions in late-onset depression. Biological Psychiatry 49, 803806.
Mazziotta, J, Toga, A, Evans, A, Fox, P, Lancaster, J, Zilles, K, Woods, R, Paus, T, Simpson, G, Pike, B, Holmes, C, Collins, L, Thompson, P, MacDonald, D, Iacoboni, M, Schormann, T, Amunts, K, Palomero-Gallagher, N, Geyer, S, Parsons, L, Narr, K, Kabani, N, Le Goualher, G, Boomsma, D, Cannon, T, Kawashima, R, Mazoyer, B (2001). A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM). Philosophical Transactions of the Royal Society B: Biological Sciences 356, 12931322.
Naranjo, CA, Tremblay, LK, Busto, UE (2001). The role of the brain reward system in depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 25, 781823.
O'Brien, J, Desmond, P, Ames, D, Schweitzer, I, Harrigan, S, Tress, B (1996). A magnetic resonance imaging study of white matter lesions in depression and Alzheimer's disease. British Journal of Psychiatry 168, 477485.
O'Brien, JT, Firbank, MJ, Krishnan, MS, van Straaten, EC, van der Flier, WM, Petrovic, K, Pantoni, L, Simoni, M, Erkinjuntti, T, Wallin, A, Wahlund, LO, Inzitari, D (2006). White matter hyperintensities rather than lacunar infarcts are associated with depressive symptoms in older people: the LADIS study. American Journal of Geriatric Psychiatry 14, 834841.
Pantoni, L, Garcia, JH (1997). Pathogenesis of leukoaraiosis: a review. Stroke 28, 652659.
Phillips, ML, Ladouceur, CD, Drevets, WC (2008). A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorder. Molecular Psychiatry 13, 829857.
Robbins, S, Evans, AC, Collins, DL, Whitesides, S (2004). Tuning and comparing spatial normalization methods. Medical Image Analysis 8, 311323.
Rogers, MA, Kasai, K, Koji, M, Fukuda, R, Iwanami, A, Nakagome, K, Fukuda, M, Kato, N (2004). Executive and prefrontal dysfunction in unipolar depression: a review of neuropsychological and imaging evidence. Neuroscience Research 50, 111.
Rolls, ET (2000). The orbitofrontal cortex and reward. Cerebral Cortex 10, 284294.
Sachdev, P, Chen, X, Wen, W (2008). White matter hyperintensities in mid-adult life. Current Opinion in Psychiatry 21, 268274.
Sachdev, PS, Parslow, R, Wen, W, Anstey, KJ, Easteal, S (2007). Sex differences in the causes and consequences of white matter hyperintensities. Neurobiology of Aging 30, 946956.
Salloway, S, Malloy, P, Duffy, JD (2001). The Frontal Lobes and Neuropsychiatric Illness, 1st edn. American Psychiatric Publishing: Washington, DC.
Sheline, YI, Price, JL, Vaishnavi, SN, Mintun, MA, Barch, DM, Epstein, AA, Wilkins, CH, Snyder, AZ, Couture, L, Schechtman, K, McKinstry, RC (2008). Regional white matter hyperintensity burden in automated segmentation distinguishes late-life depressed subjects from comparison subjects matched for vascular risk factors. American Journal of Psychiatry 165, 524532.
Steffens, DC, Conway, CR, Dombeck, CB, Wagner, HR, Tupler, LA, Weiner, RD (2001). Severity of subcortical gray matter hyperintensity predicts ECT response in geriatric depression. Journal of ECT 17, 4549.
Steffens, DC, Potter, GG, McQuoid, DR, MacFall, JR, Payne, ME, Burke, JR, Plassman, BL, Welsh-Bohmer, KA (2007). Longitudinal magnetic resonance imaging vascular changes, apolipoprotein E genotype, and development of dementia in the neurocognitive outcomes of depression in the elderly study. American Journal of Geriatric Psychiatry 15, 839849.
Swan, GE, Lessov-Schlaggar, CN (2007). The effects of tobacco smoke and nicotine on cognition and the brain. Neuropsychology Review 17, 259273.
Taylor, WD, MacFall, JR, Steffens, DC, Payne, ME, Provenzale, JM, Krishnan, KR (2003 a). Localization of age-associated white matter hyperintensities in late-life depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 27, 539544.
Taylor, WD, Steffens, DC, MacFall, JR, McQuoid, DR, Payne, ME, Provenzale, JM, Krishnan, KR (2003 b). White matter hyperintensity progression and late-life depression outcomes. Archives of General Psychiatry 60, 10901096.
Thomas, AJ, O'Brien, JT, Barber, R, McMeekin, W, Perry, R (2003). A neuropathological study of periventricular white matter hyperintensities in major depression. Journal of Affective Disorders 76, 4954.
Thomas, AJ, O'Brien, JT, Davis, S, Ballard, C, Barber, R, Kalaria, RN, Perry, RH (2002). Ischemic basis for deep white matter hyperintensities in major depression: a neuropathological study. Archives of General Psychiatry 59, 785792.
Videbech, P (1997). MRI findings in patients with affective disorder: a meta-analysis. Acta Psychiatrica Scandinavica 96, 157168.
Videbech, P, Ravnkilde, B, Gammelgaard, L, Egander, A, Clemmensen, K, Rasmussen, NA, Gjedde, A, Rosenberg, R (2004). The Danish PET/depression project: performance on Stroop's test linked to white matter lesions in the brain. Psychiatry Research 130, 117130.
Videbech, P, Ravnkilde, B, Pedersen, TH, Hartvig, H, Egander, A, Clemmensen, K, Rasmussen, NA, Andersen, F, Gjedde, A, Rosenberg, R (2002). The Danish PET/depression project: clinical symptoms and cerebral blood flow. A regions-of-interest analysis. Acta Psychiatrica Scandinavica 106, 3544.
WHO (1993). The ICD-10 Classification of Mental and Behavioural Disorders. Diagnostic Criteria for Research. World Health Organization: Geneva.
Widlöcher, DJ (1983). Psychomotor retardation: clinical, theoretical, and psychometric aspects. Psychiatric Clinics of North America 6, 2740.
Wing, JK, Sartorius, N, Üstün, TB (1998). Diagnosis and Clinical Measurement in Psychiatry. A Reference Manual for SCAN. Cambridge University Press: Cambridge.
Wolf, PA, D'Agostino, RB, Belanger, AJ, Kannel, WB (1991). Probability of stroke: a risk profile from the Framingham Study. Stroke 22, 312318.
Worsley, KJ, Liao, CH, Aston, J, Petre, V, Duncan, GH, Morales, F, Evans, AC (2002). A general statistical analysis for fMRI data. NeuroImage 15, 115.
Worsley, KJ, Marrett, S, Neelin, P, Vandal, AC, Friston, KJ, Evans, AC (1996). A unified statistical approach for determining significant signals in images of cerebral activation. Human Brain Mapping 4, 5873.



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